Genetic polymorphisms associated with rheumatoid arthritis, metods of detection and uses thereof

ABSTRACT

The present invention provides compositions and methods based on genetic polymorphisms that are associated with autoimmune disease, particularly rheumatoid arthritis. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. non-provisional application Ser. No. 12/953,833, filed Nov. 24, 2010, which is a divisional application of U.S. non-provisional application of Ser. No. 12/231,877, filed Sep. 4, 2008 (issued as U.S. Pat. No. 7,863,021 on Jan. 4, 2011), which claims priority to U.S. provisional application Ser. No. 60/935,887, filed Sep. 5, 2007, the contents of each of which are hereby incorporated by reference into this application.

FIELD OF THE INVENTION

The present invention is in the field of autoimmune disease, particularly rheumatoid arthritis (RA). In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with autoimmune disease, particularly RA. The SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the SNPs of the present invention are useful for such uses as identifying an individual who has an increased or decreased risk of developing autoimmune disease (particularly RA), for early detection of the disease, for providing clinically important information for the prevention and/or treatment of autoimmune disease, for predicting progression or recurrence of autoimmune disease, for predicting the seriousness or consequences of autoimmune disease in an individual, for determining the prognosis of an individual's recovery from autoimmune disease, for screening and selecting therapeutic agents, and for predicting a patient's response to therapeutic agents such as evaluating the likelihood of an individual responding positively to tumor necrosis factor (TNF) inhibitors, particularly for the treatment or prevention of autoimmune disease (such as RA). The SNPs disclosed herein are also useful for human identification applications. Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided.

BACKGROUND OF THE INVENTION

Autoimmune Diseases & Rheumatoid Arthritis (RA)

Autoimmune diseases are a major health issue, occurring in up to 3% of the general population (Cooper & Stroehla, 2003, Autoimmunity Rev. 2:119-125). Although the clinical phenotypes of these diseases are distinct, they share certain common elements, including geographical distributions, population frequencies, therapeutic strategies, and some clinical features which suggest potential similarities in the underlying mechanisms of these diseases. Furthermore, the aggregation of multiple autoimmune diseases in the same individual or family supports the presence of common environmental and genetic factors that predispose an individual to autoimmunity (Vyse & Todd, 1996, Cell 85:311-318; Cooper & Stroehla, 2003, Autoimmunity Rev. 2:119-125; Ueda et al., 2003, Nature 423:506-511).

Inflammatory disorders are related to autoimmune disease. Examples of autoimmune and inflammatory diseases include rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel diseases, psoriasis, thyroiditis, celiac disease, pernicious anemia, asthma, vitiligo, glomerulonephritis, Graves' disease, myocarditis, Sjogren disease, and primary systemic vasculitis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, with a prevalence of between 0.5-1% in most adult populations. It is found worldwide and affects all ethnic groups, although it is more common in Europe and the United States than in Asia (Abdel-Nasser et al., 1997, Semin. Arthritis Rheum. 27:123-140; Silman & Hochberg, 1993, Rheumatoid Arthritis, Epidemiology of the Rheumatic Diseases, Oxford University Press, pp. 7-68) and there is a gradient in Europe with a higher prevalence in the north (Cimmino et al., 1998, Ann. Rheum. Diseases 57:315-318). RA can also occur in any age group. Onset is typically between the ages of 40 and 60 years, and the incidence increases with age until approximately 70-80 years, at which point it declines (Abdel-Nasser et al., 1997, Semin. Arthritis Rheum. 27: 123-140; Silman & Hochberg, 1993, Epidemiology of the Rheumatic Diseases. Oxford University Press. pp. 7-68). RA is two to three times more common in women than men, depending on age (Linos et al., 1980, J. Chronic Diseases 33:73-77). The observations that (i) women in the postpartum period are at increased risk for RA onset and (ii) women with RA commonly experience remission during pregnancy followed by postpartum relapse (Barrett et al., 1999, Arhritis Rheum. 42:1219-1227) suggest that hormones play a role in disease onset.

RA is a chronic, progressive disease characterized by the infiltration of activated lymphocytes and macrophages into the synovial lining of the affected joint. These cells produce cytokines and degradative enzymes, which mediate inflammation and destruction of the joint architecture, often leading to permanent disability. RA is a systemic disease; extra-articular manifestations are often present and can range from relatively minor problems, such as rheumatoid nodules, to life-threatening organ disease.

Clinically, RA varies from a very mild to a severely disabling disease with upwards of one in 20 patients progressing to severe, erosive disease. Joint damage occurs early in disease with the greatest progression to joint abnormalities taking place during the first six years. Within three years of disease onset, as many as 70% of patients show some radiographic evidence of joint damage (Lipsky et al., 1994, Rheumatoid Arthritis, Harrison's Principles of Internal Medicine, 13th ed. New York, McGraw-Hill, Inc., pp. 1648-1655). At present, there is no cure for RA, and the joint damage is irreversible.

Although the course of RA is highly variable, most patients with clinical, persistent RA eventually develop debilitating joint damage and deformation, resulting in progressive functional limitation. Consequently, RA is considered a highly disabling disease with a considerable economic impact that some liken to that of coronary artery disease (Allaire et al., 1994, Pharmacoeconomics 6:513-522). A 1993 study in the U.S. estimated total annual direct costs of $5275 per patient with indirect costs as high as $21,000 per year (Merkesdal et al., 2001, Arthritis Rheum. 44:528-534).

RA is thought to be precipitated by the interplay of environmental and genetic factors. Although several environmental triggers have been suggested, such as infection (Harris, 1990, N. Engl. J. Med. 322:1277-1289), immunization (Symmons and Chakravarty, 1993, Ann. Rheum. Dis. 52:843-844), diet (Shapiro et al., 1996, Epidemiology 7:256-263), and smoking (Symmons et al., 1997, Arthritis Rheum. 40:1955-1961), none have been established. A genetic component to RA susceptibility has long been indicated by data from twin and family studies. It is estimated that the concordance between monozygotic twins is in the range of 12-15% while the prevalence in siblings of RA probands is approximately 2-4%, both well above the estimated background population prevalence of 0.5-1% (Seldin et al., 1999, Arthritis Rheum. 42:1071-1079). From these data, the disease heritability has been estimated at approximately 60% (MacGregor et al., 2000, Arthritis Rheum. 43:30-37) while the relative recurrence risk for siblings (λs) of probands with RA is estimated at between 5 and 10 (Seldin et al. 1999; Jawaheer et al., 2001, Am. J. Hum. Genet. 68:927-936).

The increasing availability of specific therapies that can halt disease progression has magnified the need for accurate early diagnosis of RA (Maini et al., 1999, Lancet 354:1932-1939; Lipsky et al., 2000, N. Engl. J. Med. 343: 1594-1602; Weinblatt et al., 1999, N. Engl. J. Med. 340: 253-259). The most commonly used diagnostic criteria are those adopted by the American College of Rheumatology in 1987 (Arnett et al., 1988, Arthritis Rheum. 31: 315-324), which are based on a combination of clinical, laboratory and radiological assessments. A patient is classified as having RA if he or she satisfies at least four of the following seven criteria: (i) morning stiffness lasting at least one hour; (ii) arthritis of three or more joint areas; (iii) arthritis of hand joints; (iv) symmetric arthritis; (v) rheumatoid nodules; (vi) presence of serum rheumatoid factor (RF); and (vii) radiographic changes in hand or wrist joints. Using these criteria, a trained rheumatologist can usually diagnose RA in individuals who have had disease for more than 12 weeks (Harrison et al., 1998, J. Rheumatol. 25: 2324-2330). However, these criteria are largely ineffective for patients during early stages of the disease, such as during the first 12 weeks of disease (Green et al., 1999, Arthritis Rheum. 42: 2184-2188), during which time irreversible joint damage has already begun, and cannot predict which patients will develop severe erosive disease and therefore benefit from aggressive early disease modifying therapy.

Early initiation of therapy can provide considerable benefit, not only by reducing pain and inflammation but also by reducing or eliminating the loss of function that accompanies persistent RA, especially when therapy is administered prior to the occurrence of irreversible joint damage. Consequently, there is a need for novel diagnostic markers that, for example, enable the detection of RA, particularly at an early stage, or that enable the identification of individuals who are predisposed to developing RA.

Single Nucleotide Polymorphisms (SNPs)

The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor genetic sequences. Gusella, Ann Rev Biochem 55:831-854 (1986). A variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers an evolutionary advantage to individual members of a species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the environment. For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal. In many cases, both progenitor and variant forms survive and co-exist in a species population. The coexistence of multiple forms of a genetic sequence segregating at appreciable frequencies is defined as a genetic polymorphism, which includes single nucleotide polymorphisms (SNPs).

Approximately 90% of all genetic polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. The SNP position (interchangeably referred to herein as SNP, SNP site, SNP locus, SNP marker, or marker) is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). An individual may be homozygous or heterozygous for an allele at each SNP position. A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at the polymorphic site. Substitutions can be transitions or transversions. A transition is the replacement of one purine nucleotide by another purine nucleotide, or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine, or vice versa. A SNP may also be a single base insertion or deletion variant referred to as an “indel.” Weber et al., “Human diallelic insertion/deletion polymorphisms,” Am J Hum Genet. 71(4):854-62 (October 2002).

A synonymous codon change, or silent mutation/SNP (terms such as “SNP,” “polymorphism,” “mutation,” “mutant,” “variation,” and “variant” are used herein interchangeably), is one that does not result in a change of amino acid due to the degeneracy of the genetic code. A substitution that changes a codon coding for one amino acid to a codon coding for a different amino acid (i.e., a non-synonymous codon change) is referred to as a missense mutation. A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein. A read-through mutation is another type of non-synonymous codon change that causes the destruction of a stop codon, thereby resulting in an extended polypeptide product. While SNPs can be bi-, tri-, or tetra-allelic, the vast majority of SNPs are bi-allelic, and are thus often referred to as “bi-allelic markers,” or “di-allelic markers.”

As used herein, references to SNPs and SNP genotypes include individual SNPs and/or haplotypes, which are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs, and therefore may provide increased diagnostic accuracy in some cases. Stephens et al., Science 293:489-493 (July 2001).

Causative SNPs are those SNPs that produce alterations in gene expression or in the expression, structure, and/or function of a gene product, and therefore are most predictive of a possible clinical phenotype. One such class includes SNPs falling within regions of genes encoding a polypeptide product, i.e. cSNPs. These SNPs may result in an alteration of the amino acid sequence of the polypeptide product (i.e., non-synonymous codon changes) and give rise to the expression of a defective or other variant protein. Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product. Such variant products can result in a pathological condition, e.g., genetic disease. Examples of genes in which a SNP within a coding sequence causes a genetic disease include sickle cell anemia and cystic fibrosis.

Causative SNPs do not necessarily have to occur in coding regions; causative SNPs can occur in, for example, any genetic region that can ultimately affect the expression, structure, and/or activity of the protein encoded by a nucleic acid. Such genetic regions include, for example, those involved in transcription, such as SNPs in transcription factor binding domains, SNPs in promoter regions, in areas involved in transcript processing, such as SNPs at intron-exon boundaries that may cause defective splicing, or SNPs in mRNA processing signal sequences such as polyadenylation signal regions. Some SNPs that are not causative SNPs nevertheless are in close association with, and therefore segregate with, a disease-causing sequence. In this situation, the presence of a SNP correlates with the presence of, or predisposition to, or an increased risk in developing the disease. These SNPs, although not causative, are nonetheless also useful for diagnostics, disease predisposition screening, and other uses.

An association study of a SNP and a specific disorder involves determining the presence or frequency of the SNP allele in biological samples from individuals with the disorder of interest, such as autoimmune disease, and comparing the information to that of controls (i.e., individuals who do not have the disorder; controls may be also referred to as “healthy” or “normal” individuals) who are preferably of similar age and race. The appropriate selection of patients and controls is important to the success of SNP association studies. Therefore, a pool of individuals with well-characterized phenotypes is extremely desirable.

A SNP may be screened in diseased tissue samples or any biological sample obtained from a diseased individual, and compared to control samples, and selected for its increased (or decreased) occurrence in a specific pathological condition, such as pathologies related to autoimmune disease and in particular, RA. Once a statistically significant association is established between one or more SNP(s) and a pathological condition (or other phenotype) of interest, then the region around the SNP can optionally be thoroughly screened to identify the causative genetic locus/sequence(s) (e.g., causative SNP/mutation, gene, regulatory region, etc.) that influences the pathological condition or phenotype. Association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families (linkage studies).

Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous. There is a continuing need to improve pharmaceutical agent design and therapy. In that regard, SNPs can be used to identify patients most suited to therapy with particular pharmaceutical agents (this is often termed “pharmacogenomics”). Similarly, SNPs can be used to exclude patients from certain treatment due to the patient's increased likelihood of developing toxic side effects or their likelihood of not responding to the treatment. Pharmacogenomics can also be used in pharmaceutical research to assist the drug development and selection process. Linder et al., Clinical Chemistry 43:254 (1997); Marshall, Nature Biotechnology 15:1249 (1997); International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et al., Nature Biotechnology 16:3 (1998).

SUMMARY OF THE INVENTION

The present invention relates to the identification of SNPs, as well as unique combinations of such SNPs and haplotypes of SNPs, that are associated with autoimmune disease, particularly rheumatoid arthritis (RA). The polymorphisms disclosed herein are directly useful as targets for the design of diagnostic and prognostic reagents and the development of therapeutic and preventive agents for use in the diagnosis, prognosis, treatment, and/or prevention of autoimmune disease (particularly RA), as well as for predicting a patient's response to therapeutic agents such as tumor necrosis factor (TNF) inhibitors, particularly for the treatment or prevention of autoimmune disease.

Based on the identification of SNPs associated with autoimmune disease (particularly RA), the present invention also provides methods of detecting these variants as well as the design and preparation of detection reagents needed to accomplish this task. The invention specifically provides, for example, SNPs associated with autoimmune disease (particularly RA), isolated nucleic acid molecules (including DNA and RNA molecules) containing these SNPs, variant proteins encoded by nucleic acid molecules containing such SNPs, antibodies to the encoded variant proteins, computer-based and data storage systems containing the novel SNP information, methods of detecting these SNPs in a test sample, methods of identifying individuals who have an altered (i.e., increased or decreased) risk of developing autoimmune disease (particularly RA), methods for determining the risk of an individual for recurring autoimmune disease (e.g., recurrent RA), methods for prognosing the severity or consequences of autoimmune disease, methods of treating an individual who has an increased risk for autoimmune disease, and methods for identifying individuals (e.g., determining a particular individual's likelihood) who have an altered (i.e., increased or decreased) likelihood of responding to drug treatment, particularly drug treatment of autoimmune disease (e.g., treatment or prevention of RA), based on the presence or absence of one or more particular nucleotides (alleles) at one or more SNP sites disclosed herein or the detection of one or more encoded variant products (e.g., variant mRNA transcripts or variant proteins), methods of identifying individuals who are more or less likely to respond to a treatment (or more or less likely to experience undesirable side effects from a treatment), methods of screening for compounds useful in the treatment or prevention of a disorder associated with a variant gene/protein, compounds identified by these methods, methods of treating or preventing disorders mediated by a variant gene/protein, methods of using the novel SNPs of the present invention for human identification, etc.

The present invention further provides methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer TNF inhibitor treatment to an individual having autoimmune disease, or who is at risk for developing autoimmune disease in the future, or who has previously had autoimmune disease, methods for selecting a particular TNF inhibitor-based treatment regimen such as dosage and frequency of administration of TNF inhibitor, or a particular form/type of TNF inhibitor such as a particular antibody, fusion protein, small molecule compound, nucleic acid agent, pharmaceutical formulation, etc., methods for administering an alternative, non-TNF inhibitor treatment to individuals who are predicted to be unlikely to respond positively to TNF inhibitor treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from TNF inhibitor treatment, etc. The present invention also provides methods for selecting individuals to whom a TNF inhibitor or other therapeutic will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a TNF inhibitor or other therapeutic agent based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the TNF inhibitor treatment and/or excluding individuals from the trial who are unlikely to respond positively from the TNF inhibitor treatment based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to TNF inhibitors based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them). The present invention further provides methods for reducing an individual's risk of developing autoimmune disease (such as RA) using TNF inhibitor treatment, including preventing recurring autoimmune disease (e.g., recurrent RA) using TNF inhibitor treatment, when said individual carries one or more SNPs identified herein as being associated with autoimmune disease.

In Tables 1 and 2, the present invention provides gene information, references to the identification of transcript sequences (SEQ ID NOS:1-16), encoded amino acid sequences (SEQ ID NOS:17-32), genomic sequences (SEQ ID NOS:78-91), transcript-based context sequences (SEQ ID NOS:33-77) and genomic-based context sequences (SEQ ID NOS:92-584) that contain the SNPs of the present invention, and extensive SNP information that includes observed alleles, allele frequencies, populations/ethnic groups in which alleles have been observed, information about the type of SNP and corresponding functional effect, and, for cSNPs, information about the encoded polypeptide product. The actual transcript sequences (SEQ ID NOS:1-16), amino acid sequences (SEQ ID NOS:17-32), genomic sequences (SEQ ID NOS:78-91), transcript-based SNP context sequences (SEQ ID NOS:33-77), and genomic-based SNP context sequences (SEQ ID NOS:92-584), together with primer sequences (SEQ ID NOS:585-1004) are provided in the Sequence Listing.

In certain exemplary embodiments, the invention provides methods for identifying an individual who has an altered risk for developing autoimmune disease such as RA (including, for example, a first incidence and/or a recurrence of the disease), in which the method comprises detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-16, SEQ ID NOS:33-77, SEQ ID NOS:78-91, and SEQ ID NOS:92-584 in said individual's nucleic acids, wherein the SNP is specified in Table 1 and/or Table 2, and the presence of the SNP is indicative of an altered risk for autoimmune disease in said individual. In certain embodiments, the autoimmune disease is RA. In certain exemplary embodiments of the invention, SNPs that occur naturally in the human genome are provided as isolated nucleic acid molecules. These SNPs are associated with autoimmune disease, particular RA, such that they can have a variety of uses in the diagnosis, prognosis, treatment, and/or prevention of autoimmune disease and related pathologies, and in the treatment or prevention of autoimmune disease, particularly by using TNF inhibitors. In an alternative embodiment, a nucleic acid of the invention is an amplified polynucleotide, which is produced by amplification of a SNP-containing nucleic acid template. In another embodiment, the invention provides for a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein.

In yet another embodiment of the invention, a reagent for detecting a SNP in the context of its naturally-occurring flanking nucleotide sequences (which can be, e.g., either DNA or mRNA) is provided. In particular, such a reagent may be in the form of, for example, a hybridization probe or an amplification primer that is useful in the specific detection of a SNP of interest. In an alternative embodiment, a protein detection reagent is used to detect a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein. A preferred embodiment of a protein detection reagent is an antibody or an antigen-reactive antibody fragment. Various embodiments of the invention also provide kits comprising SNP detection reagents, and methods for detecting the SNPs disclosed herein by employing detection reagents.

In various embodiments, the present invention provides for a method of identifying an individual having an increased or decreased risk of developing autoimmune disease (e.g., RA) by detecting the presence or absence of one or more SNP alleles (or haplotypes or diplotypes) disclosed herein. In other embodiments, a method for diagnosis or prognosis of autoimmune disease (e.g., RA) by detecting the presence or absence of one or more SNP alleles (or haplotypes or diplotypes) disclosed herein is provided. The present invention also provides methods for evaluating whether an individual is likely (or unlikely) to respond to TNF inhibitor treatment, particularly TNF inhibitor treatment of autoimmune disease, by detecting the presence or absence of one or more SNP alleles (or haplotypes or diplotypes) disclosed herein.

In certain exemplary embodiments, the invention provides methods and compositions based on any of the following SNPs, individually or in any combination: rs1953126, rs10985196, rs6478486, rs4836834, rs2239657, rs7021880, rs7021049, rs10760117, rs7046030, rs12683459, rs1323472, rs942152, rs2900180, rs7026635, rs10818527, rs1609810, rs881375, and the other SNPs disclosed herein (such as the SNPs provided in any of Tables 1-7 and 9-16), as well as combinations thereof. For example, in certain exemplary embodiments, the invention provides methods for determining an individual's risk for developing autoimmune disease (particularly RA), methods for diagnosing or prognosing autoimmune disease (particularly RA), methods for predicting an individual's response to a TNF inhibitor or other drug, as well as other methods of use, by detecting which allele (e.g., nucleotide) is present at any or all of these SNPs, as well as reagents and other compositions for carrying out these methods.

In certain exemplary embodiments, the invention provides methods and compositions based on combinations consisting of, consisting essentially of, or comprising the SNPs rs2239657, rs7021880, and rs7021049, and subcombinations thereof. For example, in certain exemplary embodiments, the invention provides methods for determining an individual's risk for developing autoimmune disease, particularly RA, by detecting which allele (e.g., nucleotide) is present at any or all of SNPs rs2239657, rs7021880, and rs7021049, as well as reagents and other compositions for carrying out these methods. Similarly, the invention also provides methods such as diagnosing or prognosing autoimmune disease, particularly RA, as well as methods for predicting an individual's response to a drug, particularly a TNF inhibitor, by detecting which allele (e.g., nucleotide) is present at any or all of SNPs rs2239657, rs7021880, and rs7021049, as well as reagents and other compositions for carrying out these and other methods.

In certain further embodiments, the invention provides haplotypes consisting of, consisting essentially of, or comprising the following combinations of alleles at SNPs rs2239657, rs7021880, and rs7021049: rs2239657(A)-rs7021880(G)-rs7021049(T) as a protective haplotype, rs2239657(G)-rs7021880(C)-rs7021049(G) as a risk (predisposition) haplotype, as well as rs2239657(A)-rs7021880(G)-rs7021049(G) and rs2239657(G)-rs7021880(G)-rs7021049(G) (see, e.g., Table 10). In certain further embodiments, the invention provides diplotypes consisting of, consisting essentially of, or comprising the following combinations of alleles at SNPs rs2239657, rs7021880, and rs7021049: rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T) as a protective diplotype, rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) as a risk (predisposition) diplotype, as well as rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(G)-rs7021880(C)-rs7021049(G), particularly as a risk (predisposition) diplotype (see, e.g., Table 11).

Examples of other combinations of SNPs (such as haplotypes or diplotypes) of the invention include those consisting of, consisting essentially of, or comprising the following combinations of SNPs, as well as subcombinations of any of these SNPs: rs6478486-rs4836834-rs2239657-rs7021880-rs7021049 and rs2239657-rs7021880-rs7021049-rs2900180-rs2269066, as well as other haplotypes and diplotypes between and/or including rs10985070 and rs2900180.

In certain exemplary embodiments, the invention provides methods and compositions based on the any of the SNPs disclosed herein, particularly the TRAF1 SNPs disclosed herein (and combinations thereof such as haplotypes and diplotypes), and especially SNPs rs2239657, rs7021880, and rs7021049 (as well as subcombination thereof), in combination with PTPN22 and/or HLA-DRB1 polymorphisms, such as shown in FIG. 1 and Table 15. For example, the TRAF1 risk diplotype rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) and/or the TRAF1 protective diplotype rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T) can be detected in combination with PTPN22 and/or HLA-DRB1 polymorphisms, particularly the R620 W PTPN22 polymorphism (e.g., in which a CC genotype indicates homozygosity for the protective R620 allele, and TT and TC genotypes indicate carriage of the risk W620 allele) and/or the number of copies of the HLA-DRB1 shared epitope (e.g., 0SE, 1SE, or 2SE), such as to determine an individual's risk for developing autoimmune disease, particularly RA. For example, individuals with the protective genotype at all three loci (0SE for HLA-DRB1, CC genotype (R620 allele) for PTPN22 and the rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T) TRAF1 diplotype) have a substantially reduced predicted risk of RA compared with individuals with the risk genotype at all three loci (2SE for HLA-DRB1, TT or TC genotype (W620 allele) at PTPN22, and the rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) TRAF1 diplotype). Between these lowest and highest risk categories, risk for RA increases or decreases commensurately according to an invidual's particular combination of risk or protective genotypes at each of the TRAF1 locus (e.g., in which the rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T) diplotype indicates lower risk and the rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) diplotype indicates higher risk), the PTPN22 locus (e.g., in which a CC genotype/R620 allele indicates lower risk for RA, and at least one T nucleotide (TT or TC genotype)/W620 allele indicates higher risk for RA), and/or the HLA-DRB1 locus (e.g., in which 0SE indicates lowest risk, 1SE indicates intermediate risk, and 2SE indicates highest risk) (see FIG. 1 and Table 15 as an example).

The nucleic acid molecules of the invention can be inserted in an expression vector, such as to produce a variant protein in a host cell. Thus, the present invention also provides for a vector comprising a SNP-containing nucleic acid molecule, genetically-engineered host cells containing the vector, and methods for expressing a recombinant variant protein using such host cells. In another specific embodiment, the host cells, SNP-containing nucleic acid molecules, and/or variant proteins can be used as targets in a method for screening and identifying therapeutic agents or pharmaceutical compounds useful in the treatment or prevention of autoimmune disease (particularly RA).

An aspect of this invention is a method for treating or preventing autoimmune disease such as RA (including, for example, a first occurrence and/or a recurrence of the disease), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises administering to said human subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disease, such as by inhibiting (or stimulating) the activity of a gene, transcript, and/or encoded protein identified in Tables 1 and 2.

Another aspect of this invention is a method for identifying an agent useful in therapeutically or prophylactically treating autoimmune disease (particularly RA), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises contacting the gene, transcript, or encoded protein with a candidate agent under conditions suitable to allow formation of a binding complex between the gene, transcript, or encoded protein and the candidate agent and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.

Another aspect of this invention is a method for treating or preventing autoimmune disease (such as RA), in a human subject, in which the method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, and

(ii) administering to said subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disease, such as TNF inhibitors.

Another aspect of the invention is a method for identifying a human who is likely to benefit from TNF inhibitor treatment, in which the method comprises detecting an allele of one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele indicates that said human is likely to benefit from TNF inhibitor treatment.

Another aspect of the invention is a method for identifying a human who is likely to benefit from TNF inhibitor treatment, in which the method comprises detecting an allele of one or more SNPs that are in LD with one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele of the LD SNP indicates that said human is likely to benefit from TNF inhibitor treatment.

Many other uses and advantages of the present invention will be apparent to those skilled in the art upon review of the detailed description of the preferred embodiments herein. Solely for clarity of discussion, the invention is described in the sections below by way of non-limiting examples.

DESCRIPTION OF THE FILES CONTAINED ON THE CD-Rs

Each of the three CD-Rs contains an identical copy of each the following three text files:

1) File CD000019ORD_SEQLIST.txt provides the Sequence Listing. The Sequence Listing provides the transcript sequences (SEQ ID NOS:1-16) and protein sequences (SEQ ID NOS:17-32) as referred to in Table 1, and genomic sequences (SEQ ID NOS:78-91) as referred to in Table 2, for each autoimmune disease-associated gene (or genomic region for intergenic SNPs) that contains one or more SNPs of the present invention. Also provided in the Sequence Listing are context sequences flanking each SNP, including both transcript-based context sequences as referred to in Table 1 (SEQ ID NOS:33-77) and genomic-based context sequences as referred to in Table 2 (SEQ ID NOS:92-584). In addition, the Sequence Listing provides the primer sequences from Table 3 (SEQ ID NOS:585-1004), which are oligonucleotides that have been synthesized and used in the laboratory to assay certain SNPs disclosed herein by allele-specific PCR during the course of association studies to verify the association of these SNPs with autoimmune disease. The context sequences generally provide 100 bp upstream (5′) and 100 bp downstream (3′) of each SNP, with the SNP in the middle of the context sequence, for a total of 200 bp of context sequence surrounding each SNP.

File CD000019ORD_SEQLIST.txt is 1,595 KB in size, and was created on Aug. 29, 2008. In accordance with 37 C.F.R. §1.821(f), the information recorded on each of the CDRs submitted herewith is identical.

2) File CD000019ORD_TABLE1.txt provides Table 1. File CD000019ORD_TABLE1.txt is 51 KB in size, and was created on Aug. 28, 2008.

3) File CD000019ORD_TABLE2.txt provides Table 2. File CD000019ORD_TABLE2.txt is 390 KB in size, and was created on Aug. 29, 2008.

The material contained on the CD-R is hereby incorporated by reference pursuant to 37 CFR 1.77(b)(4).

LENGTHY TABLES The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20130315894A1). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

DESCRIPTION OF TABLE 1 AND TABLE 2

Table 1 and Table 2 (both provided on the CD-R) disclose the SNP and associated gene/transcript/protein information of the present invention. For each gene, Table 1 provides a header containing gene, transcript and protein information, followed by a transcript and protein sequence identifier (SEQ ID NO), and then SNP information regarding each SNP found in that gene/transcript including the transcript context sequence. For each gene in Table 2, a header is provided that contains gene and genomic information, followed by a genomic sequence identifier (SEQ ID NO) and then SNP information regarding each SNP found in that gene, including the genomic context sequence.

Note that SNP markers may be included in both Table 1 and Table 2; Table 1 presents the SNPs relative to their transcript sequences and encoded protein sequences, whereas Table 2 presents the SNPs relative to their genomic sequences. In some instances Table 2 may also include, after the last gene sequence, genomic sequences of one or more intergenic regions, as well as SNP context sequences and other SNP information for any SNPs that lie within these intergenic regions. Additionally, in either Table 1 or 2 a “Related Interrogated SNP” may be listed following a SNP which is determined to be in LD with that interrogated SNP according to the given Power value. SNPs can be readily cross-referenced between all Tables based on their Celera hCV (or, in some instances, hDV) identification numbers and/or public rs identification numbers, and to the Sequence Listing based on their corresponding SEQ ID NOs.

The gene/transcript/protein information includes:

-   -   a gene number (1 through n, where n=the total number of genes in         the Table),     -   a gene symbol, along with an Entrez gene identification number         (Entrez Gene database, National Center for Biotechnology         Information (NCBI), National Library of Medicine, National         Institutes of Health)     -   a gene name,     -   an accession number for the transcript (e.g., RefSeq NM number,         or a Celera hCT identification number if no RefSeq NM number is         available) (Table 1 only),     -   an accession number for the protein (e.g., RefSeq NP number, or         a Celera hCP identification number if no RefSeq NP number is         available) (Table 1 only),     -   the chromosome number of the chromosome on which the gene is         located,     -   an OMIM (“Online Mendelian Inheritance in Man” database, Johns         Hopkins University/NCBI) public reference number for the gene,         and OMIM information such as alternative gene/protein name(s)         and/or symbol(s) in the OMIM entry.

Note that, due to the presence of alternative splice forms, multiple transcript/protein entries may be provided for a single gene entry in Table 1; i.e., for a single Gene Number, multiple entries may be provided in series that differ in their transcript/protein information and sequences.

Following the gene/transcript/protein information is a transcript context sequence (Table 1), or a genomic context sequence (Table 2), for each SNP within that gene.

After the last gene sequence, Table 2 may include additional genomic sequences of intergenic regions (in such instances, these sequences are identified as “Intergenic region:” followed by a numerical identification number), as well as SNP context sequences and other SNP information for any SNPs that lie within each intergenic region (such SNPs are identified as “INTERGENIC” for SNP type).

Note that the transcript, protein, and transcript-based SNP context sequences are all provided in the Sequence Listing. The transcript-based SNP context sequences are provided in both Table 1 and also in the Sequence Listing. The genomic and genomic-based SNP context sequences are provided in the Sequence Listing. The genomic-based SNP context sequences are provided in both Table 2 and in the Sequence Listing. SEQ ID NOs are indicated in Table 1 for the transcript-based context sequences (SEQ ID NOS:33-77); SEQ ID NOs are indicated in Table 2 for the genomic-based context sequences (SEQ ID NOS:92-584).

The SNP information includes:

-   -   Context sequence (taken from the transcript sequence in Table 1,         the genomic sequence in Table 2) with the SNP represented by its         IUB code, including 100 bp upstream (5′) of the SNP position         plus 100 bp downstream (3′) of the SNP position (the         transcript-based SNP context sequences in Table 1 are provided         in the Sequence Listing as SEQ ID NOS:33-77; the genomic-based         SNP context sequences in Table 2 are provided in the Sequence         Listing as SEQ ID NOS:92-584).     -   Celera hCV internal identification number for the SNP (in some         instances, an “hDV” number is given instead of an “hCV” number).     -   The corresponding public identification number for the SNP, the         rs number.     -   “SNP Chromosome Position” indicates the nucleotide position of         the SNP along the entire sequence of the chromosome as provided         in NCBI Genome Build 36.     -   SNP position (nucleotide position of the SNP within the given         transcript sequence (Table 1) or within the given genomic         sequence (Table 2)).     -   “Related Interrogated SNP” is the interrogated SNP with which         the listed SNP is in LD at the given value of Power.     -   SNP source (may include any combination of one or more of the         following five codes, depending on which internal sequencing         projects and/or public databases the SNP has been observed in:         “Applera”=SNP observed during the re-sequencing of genes and         regulatory regions of 39 individuals, “Celera”=SNP observed         during shotgun sequencing and assembly of the Celera human         genome sequence, “Celera Diagnostics”=SNP observed during         re-sequencing of nucleic acid samples from individuals who have         a disease, “dbSNP”=SNP observed in the dbSNP public database,         “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP         observed in the Human Gene Mutation Database (HGMD) public         database, “HapMap”=SNP observed in the International HapMap         Project public database, “CSNP”=SNP observed in an internal         Applied Biosystems (Foster City, Calif.) database of coding SNPS         (cSNPs).

Note that multiple “Applera” source entries for a single SNP indicate that the same SNP was covered by multiple overlapping amplification products and the re-sequencing results (e.g., observed allele counts) from each of these amplification products is being provided.

-   -   Population/allele/allele count information in the format of         [population1(first_allele,count|second_allele,count)population2(first_allele,count|second_allele,count)total(first_allele,total         count|second_allele,total count)]. The information in this field         includes populations/ethnic groups in which particular SNP         alleles have been observed (“cau”=Caucasian, “his”=Hispanic,         “chn”=Chinese, and “afr”=African-American, “jpn”=Japanese,         “ind”=Indian, “mex”=Mexican, “ain”=“American Indian,         “cra”=Celera donor, “no_pop”=no population information         available), identified SNP alleles, and observed allele counts         (within each population group and total allele counts), where         available [“-” in the allele field represents a deletion allele         of an insertion/deletion (“indel”) polymorphism (in which case         the corresponding insertion allele, which may be comprised of         one or more nucleotides, is indicated in the allele field on the         opposite side of the “|”); “-” in the count field indicates that         allele count information is not available]. For certain SNPs         from the public dbSNP database, population/ethnic information is         indicated as follows (this population information is publicly         available in dbSNP): “HISP1”=human individual DNA (anonymized         samples) from 23 individuals of self-described HISPANIC         heritage; “PAC1”=human individual DNA (anonymized samples) from         24 individuals of self-described PACIFIC RIM heritage;         “CAUC1”=human individual DNA (anonymized samples) from 31         individuals of self-described CAUCASIAN heritage; “AFR1”=human         individual DNA (anonymized samples) from 24 individuals of         self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human         individual DNA (anonymized samples) from 102 individuals of         self-described heritage; “PA130299515”; “SC_(—)12_A”=SANGER 12         DNAs of Asian origin from Corielle cell repositories, 6 of which         are male and 6 female; “SC_(—)12_C”=SANGER 12 DNAs of Caucasian         origin from Corielle cell repositories from the CEPH/UTAH         library, six male and six female; “SC_(—)12_AA”=SANGER 12 DNAs         of African-American origin from Corielle cell repositories 6 of         which are male and 6 female; “SC_(—)95_C”=SANGER 95 DNAs of         Caucasian origin from Corielle cell repositories from the         CEPH/UTAH library; and “SC_(—)12_CA”=Caucasians—12 DNAs from         Corielle cell repositories that are from the CEPH/UTAH library,         six male and six female.

Note that for SNPs of “Applera” SNP source, genes/regulatory regions of 39 individuals (20 Caucasians and 19 African Americans) were re-sequenced and, since each SNP position is represented by two chromosomes in each individual (with the exception of SNPs on X and Y chromosomes in males, for which each SNP position is represented by a single chromosome), up to 78 chromosomes were genotyped for each SNP position. Thus, the sum of the African-American (“afr”) allele counts is up to 38, the sum of the Caucasian allele counts (“cau”) is up to 40, and the total sum of all allele counts is up to 78.

Note that semicolons separate population/allele/count information corresponding to each indicated SNP source; i.e., if four SNP sources are indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” then population/allele/count information is provided in four groups which are separated by semicolons and listed in the same order as the listing of SNP sources, with each population/allele/count information group corresponding to the respective SNP source based on order; thus, in this example, the first population/allele/count information group would correspond to the first listed SNP source (Celera) and the third population/allele/count information group separated by semicolons would correspond to the third listed SNP source (HGBASE); if population/allele/count information is not available for any particular SNP source, then a pair of semicolons is still inserted as a place-holder in order to maintain correspondence between the list of SNP sources and the corresponding listing of population/allele/count information.

-   -   SNP type (e.g., location within gene/transcript and/or predicted         functional effect) [“MIS-SENSE MUTATION”=SNP causes a change in         the encoded amino acid (i.e., a non-synonymous coding SNP);         “SILENT MUTATION”=SNP does not cause a change in the encoded         amino acid (i.e., a synonymous coding SNP); “STOP CODON         MUTATION”=SNP is located in a stop codon; “NONSENSE         MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is         located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a         3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a         putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative         3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice         site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located         in an acceptor splice site (3′ intron boundary); “CODING         REGION”=SNP is located in a protein-coding region of the         transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is         located in an intron; “hmCS”=SNP is located in a human-mouse         conserved segment; “TFBS”=SNP is located in a transcription         factor binding site; “UNKNOWN”=SNP type is not defined;         “INTERGENIC”=SNP is intergenic, i.e., outside of any gene         boundary].     -   Protein coding information (Table 1 only), where relevant, in         the format of [protein SEQ ID NO, amino acid position, (amino         acid-1, codon1) (amino acid-2, codon2)]. The information in this         field includes SEQ ID NO of the encoded protein sequence,         position of the amino acid residue within the protein identified         by the SEQ ID NO that is encoded by the codon containing the         SNP, amino acids (represented by one-letter amino acid codes)         that are encoded by the alternative SNP alleles (in the case of         stop codons, “X” is used for the one-letter amino acid code),         and alternative codons containing the alternative SNP         nucleotides which encode the amino acid residues (thus, for         example, for missense mutation-type SNPs, at least two different         amino acids and at least two different codons are generally         indicated; for silent mutation-type SNPs, one amino acid and at         least two different codons are generally indicated, etc.). In         instances where the SNP is located outside of a protein-coding         region (e.g., in a UTR region), “None” is indicated following         the protein SEQ ID NO.

DESCRIPTION OF TABLE 3

Table 3 provides sequences (SEQ ID NOS:585-1004) of primers that may be used to assay the SNPs disclosed herein by allele-specific PCR or other methods, such as for uses related to autoimmune disease, particularly RA (see Examples section).

Table 3 provides the following:

-   -   the column labeled “Marker” provides an hCV identification         number for each SNP that can be detected using the corresponding         primers.     -   the column labeled “Alleles” designates the two alternative         alleles (i.e., nucleotides) at the SNP site. These alleles are         targeted by the allele-specific primers (the allele-specific         primers are shown as Primer 1 and Primer 2). Note that alleles         may be presented in Table 3 based on a different orientation         (i.e., the reverse complement) relative to how the same alleles         are presented in Tables 1-2.     -   the column labeled “Primer 1 (Allele-Specific Primer)” provides         an allele-specific primer that is specific for an allele         designated in the “Alleles” column.     -   the column labeled “Primer 2 (Allele-Specific Primer)” provides         an allele-specific primer that is specific for the other allele         designated in the “Alleles” column.

the column labeled “Common Primer” provides a common primer that is used in conjunction with each of the allele-specific primers (i.e., Primer 1 and Primer 2) and which hybridizes at a site away from the SNP position.

All primer sequences are given in the 5′ to 3′ direction.

Each of the nucleotides designated in the “Alleles” column matches or is the reverse complement of (depending on the orientation of the primer relative to the designated allele) the 3′ nucleotide of the allele-specific primer (i.e., either Primer 1 or Primer 2) that is specific for that allele.

DESCRIPTION OF TABLE 4

Table 4 provides a list of LD SNPs that are related to and derived from certain interrogated SNPs. The interrogated SNPs, which are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 4, are statistically significantly associated with autoimmune disease, especially RA, as described and shown herein, particularly in Tables 5-16 and in the Examples section below. The LD SNPs are provided as an example of SNPs which can also serve as markers for disease association based on their being in LD with an interrogated SNP. The criteria and process of selecting such LD SNPs, including the calculation of the r² value and the threshold r² value, are described in Example 2, below.

In Table 4, the column labeled “Interrogated SNP” presents each marker as identified by its unique hCV identification number. The column labeled “Interrogated rs” presents the publicly known rs identification number for the corresponding hCV number. The column labeled “LD SNP” presents the hCV numbers of the LD SNPs that are derived from their corresponding interrogated SNPs. The column labeled “LD SNP rs” presents the publicly known rs identification number for the corresponding hCV number. The column labeled “Power” presents the level of power where the r² threshold is set. For example, when power is set at 0.51, the threshold r² value calculated therefrom is the minimum r² that an LD SNP must have in reference to an interrogated SNP, in order for the LD SNP to be classified as a marker capable of being associated with a disease phenotype at greater than 51% probability. The column labeled “Threshold r²” presents the minimum value of r² that an LD SNP must meet in reference to an interrogated SNP in order to qualify as an LD SNP. The column labeled “r²” presents the actual r² value of the LD SNP in reference to the interrogated SNP to which it is related.

DESCRIPTION OF TABLES 5-16

Tables 5-16 provide the results of statistical analyses for SNPs disclosed in Tables 1 and 2 (SNPs can be cross-referenced between all the tables herein based on their hCV and/or rs identification numbers). The results shown in Tables 5-16 provide support for the association of these SNPs with autoimmune disease, particularly RA.

Tables 5, 6, and 7 provide minor allele frequencies and allele-based association of chromosome 9q33 SNPs with RA for Sample Set 1 (Table 5), Sample Set 2 (Table 6), and Sample Set 3 (Table 7).

Table 8 provides demographic and clinical information for Sample Sets 1, 2, and 3.

Table 9 provides results of combined analysis of 43 chromosome 9q33.2 SNPs genotyped in all three RA sample sets.

Table 10 provides three-SNP haplotypes for LD Block 1.

Table 11 provides diplotype analysis for the TRAF1-region SNPs rs2239657, rs7021880, and rs7021049.

Table 12 provides genotype counts for rs2239657, rs7021880, and rs7021049, stratified by the presence of rheumatoid factor.

Table 13 provides results of pairwise logistic regression analysis for 27 chromosome 9q33.2 SNPs.

Table 14 provides global P-values for backwards and forwards models using logistic regression.

Table 15 provides RA risk estimates for three loci—HLA-SE, PTPN22, and TRAF1—assuming a disease prevalence of 1%, 10% and 30%.

Table 16 provides HapMap SNPs in high linkage disequilibrium (r²>0.85) with rs7021049 and rs2239657.

Throughout Tables 5-16, “OR” refers to the odds ratio, “95% CI” refers to the 95% confidence interval for the odds ratio, and OR_(common) and P_(comb) refer to the odds ratio and p-value, respectively, from a combined analysis. Odds ratios (OR) that are greater than one indicate that a given allele (or combination of alleles such as a haplotype or diplotype) is a risk allele (which may also be referred to as a susceptibility allele), whereas odds ratios or hazard ratios that are less than one indicate that a given allele is a non-risk allele (which may also be referred to as a protective allele). For a given risk allele, the other alternative allele at the SNP position (which can be derived from the information provided in Tables 1-2, for example) may be considered a non-risk allele. For a given non-risk allele, the other alternative allele at the SNP position may be considered a risk allele.

Thus, with respect to disease risk (e.g., autoimmune disease such as RA), if the odds ratio for a particular allele at a SNP position is greater than one, this indicates that an individual with this particular allele has a higher risk for the disease than an individual who has the other allele at the SNP position. In contrast, if the odds ratio for a particular allele is less than one, this indicates that an individual with this particular allele has a reduced risk for the disease compared with an individual who has the other allele at the SNP position.

DESCRIPTION OF THE FIGURE

FIG. 1 shows the relative risk for RA plotted as a function of the genetic load of three validated RA risk variants in HLA-DRB1, PTPN22 and TRAF1. Individuals are classified according to the number of copies of the HLA-DRB1 shared epitope (0, 1 and 2) (SE-positive HLA-DRB1 alleles found in this sample set were: 0101, 0102, 0401, 0404, 0405, 0408 and 1001), carriage of the W620 PTPN22 missense SNP (TT+CT vs CC) and diplotypes at the TRAF1 SNPs, rs2239657, rs2021880 and rs7021049. The frequency of each combination of markers in cases and controls is indicated atop each bar.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides SNPs associated with autoimmune disease, particularly rheumatoid arthritis (RA). The present invention further provides nucleic acid molecules containing these SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The SNPs disclosed herein are useful for diagnosing, prognosing, screening for, and evaluating predisposition to autoimmune disease and related pathologies in humans. The SNPs disclosed herein may be used for predicting, screening for, and evaluating response to tumor necrosis factor (TNF) inhibitors, particularly treatment or prevention of autoimmune disease using TNF inhibitors, in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic and preventive agents.

A large number of SNPs have been identified from re-sequencing DNA from 39 individuals, and they are indicated as “Applera” SNP source in Tables 1-2. Their allele frequencies observed in each of the Caucasian and African-American ethnic groups are provided. Additional SNPs included herein were previously identified during “shotgun” sequencing and assembly of the human genome, and they are indicated as “Celera” SNP source in Tables 1 and 2. Furthermore, the information provided in Tables 1 and 2, particularly the allele frequency information obtained from 39 individuals and the identification of the precise position of each SNP within each gene/transcript, allows haplotypes (i.e., groups of SNPs that are co-inherited) to be readily inferred. The present invention encompasses SNP haplotypes, as well as individual SNPs.

Thus, the present invention provides individual SNPs associated with autoimmune disease (particularly RA), as well as combinations of SNPs and haplotypes, polymorphic/variant transcript sequences (SEQ ID NOS:1-16) and genomic sequences (SEQ ID NOS:78-91) containing SNPs, encoded amino acid sequences (SEQ ID NOS:17-32), and both transcript-based SNP context sequences (SEQ ID NOS:33-77) and genomic-based SNP context sequences (SEQ ID NOS:92-584) (transcript sequences, protein sequences, and transcript-based SNP context sequences are provided in Table 1 and the Sequence Listing; genomic sequences and genomic-based SNP context sequences are provided in Table 2 and the Sequence Listing), methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing autoimmune disease, methods of determining if an individual is likely to respond to a particular treatment such as TNF inhibitors (particularly for treating or preventing autoimmune disease), methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as autoimmune disease, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment/preventive strategy or therapeutic agent, methods of treating or preventing a disorder associated with a variant gene/protein, and methods of using the SNPs of the present invention for human identification.

The present invention further provides methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer a TNF inhibitor to an individual having autoimmune disease, or who is at risk for developing autoimmune disease in the future, or who has previously had autoimmune disease, methods for selecting a particular TNF inhibitor-based treatment regimen such as dosage and frequency of administration of TNF inhibitor, or a particular form/type of TNF inhibitor such as a particular antibody, fusion protein, small molecule compound, nucleic acid agent, pharmaceutical formulation, etc., methods for administering an alternative, non-TNF inhibitor treatment to individuals who are predicted to be unlikely to respond positively to TNF inhibitor treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from TNF inhibitor treatment, etc. The present invention also provides methods for selecting individuals to whom a TNF inhibitor or other therapeutic will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a TNF inhibitor or other therapeutic agent based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the TNF inhibitor treatment and/or excluding individuals from the trial who are unlikely to respond positively from the TNF inhibitor treatment based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to TNF inhibitors based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them).

The present invention may include novel SNPs associated with autoimmune disease, particularly RA, as well as SNPs that were previously known in the art, but were not previously known to be associated with autoimmune disease such as RA. Accordingly, the present invention may provide novel compositions and methods based on novel SNPs disclosed herein, and may also provide novel methods of using known, but previously unassociated, SNPs in methods relating to, for example, evaluating an individual's likelihood of having or developing autoimmune disease (particularly RA), predicting the likelihood of an individual experiencing a recurrence of autoimmune disease (e.g., experiencing recurrent RA), prognosing the severity of autoimmune disease in an individual, or prognosing an individual's recovery from autoimmune disease, and methods relating to evaluating an individual's likelihood of responding to TNF inhibitor treatment (particularly TNF inhibitor treatment, including preventive treatment, of autoimmune disease). In Tables 1 and 2, known SNPs are identified based on the public database in which they have been observed, which is indicated as one or more of the following SNP types: “dbSNP”=SNP observed in dbSNP, “HGBASE”=SNP observed in HGBASE, and “HGMD”=SNP observed in the Human Gene Mutation Database (HGMD).

Particular SNP alleles of the present invention can be associated with either an increased risk of having or developing autoimmune disease (e.g., RA) or increased likelihood of responding to a treatment (particularly TNF inhibitor treatment, including preventive treatment, of autoimmune disease), or a decreased risk of having or developing autoimmune disease or decreased likelihood of responding to a treatment (such as a TNF inhibitor). Thus, whereas certain SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of an increased risk of having or developing autoimmune disease (e.g., RA) or increased likelihood of responding to TNF inhibitor treatment, other SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of a decreased risk of having or developing autoimmune disease or decreased likelihood of responding to TNF inhibitor treatment. Similarly, particular SNP alleles of the present invention can be associated with either an increased or decreased likelihood of having a recurrence of autoimmune disease (e.g., recurrent RA), of fully recovering from autoimmune disease, of experiencing toxic effects from a particular treatment or therapeutic compound, etc. The term “altered” may be used herein to encompass either of these two possibilities (e.g., an increased or a decreased risk/likelihood). SNP alleles that are associated with a decreased risk of having or developing autoimmune disease (such as RA) may be referred to as “protective” alleles, and SNP alleles that are associated with an increased risk of having or developing autoimmune disease may be referred to as “susceptibility” alleles, “risk” alleles, or “risk factors”.

Those skilled in the art will readily recognize that nucleic acid molecules may be double-stranded molecules and that reference to a particular site on one strand refers, as well, to the corresponding site on a complementary strand. In defining a SNP position, SNP allele, or nucleotide sequence, reference to an adenine, a thymine (uridine), a cytosine, or a guanine at a particular site on one strand of a nucleic acid molecule also defines the thymine (uridine), adenine, guanine, or cytosine (respectively) at the corresponding site on a complementary strand of the nucleic acid molecule. Thus, reference may be made to either strand in order to refer to a particular SNP position, SNP allele, or nucleotide sequence. Probes and primers, may be designed to hybridize to either strand and SNP genotyping methods disclosed herein may generally target either strand. Throughout the specification, in identifying a SNP position, reference is generally made to the protein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the present invention include peptides, polypeptides, proteins, or fragments thereof, that contain at least one amino acid residue that differs from the corresponding amino acid sequence of the art-known peptide/polypeptide/protein (the art-known protein may be interchangeably referred to as the “wild-type,” “reference,” or “normal” protein). Such variant peptides/polypeptides/proteins can result from a codon change caused by a nonsynonymous nucleotide substitution at a protein-coding SNP position (i.e., a missense mutation) disclosed by the present invention. Variant peptides/polypeptides/proteins of the present invention can also result from a nonsense mutation (i.e., a SNP that creates a premature stop codon, a SNP that generates a read-through mutation by abolishing a stop codon), or due to any SNP disclosed by the present invention that otherwise alters the structure, function, activity, or expression of a protein, such as a SNP in a regulatory region (e.g. a promoter or enhancer) or a SNP that leads to alternative or defective splicing, such as a SNP in an intron or a SNP at an exon/intron boundary. As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably.

As used herein, an “allele” may refer to a nucleotide at a SNP position (wherein at least two alternative nucleotides are present in the population at the SNP position, in accordance with the inherent definition of a SNP) or may refer to an amino acid residue that is encoded by the codon which contains the SNP position (where the alternative nucleotides that are present in the population at the SNP position form alternative codons that encode different amino acid residues). An “allele” may also be referred to herein as a “variant”. Also, an amino acid residue that is encoded by a codon containing a particular SNP may simply be referred to as being encoded by the SNP.

A phrase such as “as represented by”, “as shown by”, “as symbolized by”, or “as designated by” may be used herein to refer to a SNP within a sequence (e.g., a polynucleotide context sequence surrounding a SNP), such as in the context of “a polymorphism as represented by position 101 of SEQ ID NO:X or its complement”. Typically, the sequence surrounding a SNP may be recited when referring to a SNP, however the sequence is not intended as a structural limitation beyond the specific SNP position itself. Rather, the sequence is recited merely as a way of referring to the SNP (in this example, “SEQ ID NO:X or its complement” is recited in order to refer to the SNP located at position 101 of SEQ ID NO:X, but SEQ ID NO:X or its complement is not intended as a structural limitation beyond the specific SNP position itself). A SNP is a variation at a single nucleotide position and therefore it is customary to refer to context sequence (e.g., SEQ ID NO:X in this example) surrounding a particular SNP position in order to uniquely identify and refer to the SNP. Alternatively, a SNP can be referred to by a unique identification number such as a public “rs” identification number or an internal “hCV” identification number, such as provided herein for each SNP (e.g., in Tables 1-2). For example, in the instant application, “rs2239657”, “hCV16175379”, and “position 101 of SEQ ID NO:526” all refer to the same SNP.

As used herein, the term “benefit” (with respect to a preventive or therapeutic drug treatment) is defined as achieving a reduced risk for a disease that the drug is intended to treat or prevent (e.g., autoimmune disease such as RA) by administrating the drug treatment, compared with the risk for the disease in the absence of receiving the drug treatment (or receiving a placebo in lieu of the drug treatment) for the same genotype. The term “benefit” may be used herein interchangeably with terms such as “respond positively” or “positively respond”.

As used herein, the terms “drug” and “therapeutic agent” are used interchangeably, and may include, but are not limited to, small molecule compounds, biologics (e.g., antibodies, proteins, protein fragments, fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g., antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc., which may be used for therapeutic and/or preventive treatment of a disease (e.g., autoimmune disease such as RA).

As used herein, “related pathologies” (e.g., in the context of “autoimmune disease and related pathologies”) includes inflammatory disorders.

The various methods described herein, such as correlating the presence or absence of a polymorphism with an altered (e.g., increased or decreased) risk (or no altered risk) for autoimmune disease such as RA (and/or correlating the presence or absence of a polymorphism with the predicted response of an individual to a drug such as a TNF inhibitor), can be carried out by automated methods such as by using a computer (or other apparatus/devices such as biomedical devices, laboratory instrumentation, or other apparatus/devices having a computer processor) programmed to carry out any of the methods described herein. For example, computer software (which may be interchangeably referred to herein as a computer program) can perform the step of correlating the presence or absence of a polymorphism in an individual with an altered (e.g., increased or decreased) risk (or no altered risk) for autoimmune disease (particularly RA) for the individual. Computer software can also perform the step of correlating the presence or absence of a polymorphism in an individual with the predicted response of the invididual to a drug such as a TNF inhibitor.

Therapeutics and Pharmacogenomics in Autoimmune Disease

Exemplary embodiments of the invention provide SNPs in (or in the vicinity of) TRAF1 and other genes (e.g., PHF19 and C5) that are associated with RA (as shown in the tables and described in the Examples section below, for example). These SNPs have a variety of therapeutic and pharmacogenomic uses related to the treatment of RA, as well as other autoimmune (and inflammatory) disorders. The RA-associated SNPs provided herein may be used, for example, to determine variability between different individuals in their response to RA therapy or other autoimmune (or inflammatory) disease therapy such as to predict whether an individual will respond positively to a particular therapy, to determine the most effective therapeutic agent (e.g., antibody, therapeutic protein or fusion protein, small molecule compound, nucleic acid agent, etc.) to use to treat an individual, to determine whether a particular therapeutic agent should or should not be administered to an individual (e.g., by predicting whether the individual is likely to positively respond to the therapy or by predicting whether the individual will experience toxic or other undesirable side effects or is unlikely to respond to the therapy), or to determine the therapeutic regimen to use for an individual such as the dosage or frequency of dosing of a therapeutic agent for a particular individual.

TNF inhibitors are an example of therapeutic agents for the treatment of RA or other autoimmune (or inflammatory) disorders which the SNPs provided herein can be used in conjunction with (e.g., to predict an individual's responsiveness). For example, TRAF1 SNP alleles disclosed herein may be associated with variability between individuals in their response to TNF inhibitors. Examples of TNF inhibitors include, but are not limited to, the monoclonal antibodies infliximab (Remicade®), adalimumab (Humira®), and golimumab (CNTO 148), and the fusion protein etanercept (Enbrel®).

Therapeutic agents that directly modulate (e.g., inhibit or stimulate) TRAF1 (or other TRAF proteins, or any of the other RA-associated genes disclosed herein such as PHF19 and C5) may be used to treat RA or other autoimmune/inflammatory disorders and, furthermore, therapeutic agents that target proteins that interact with TRAF1 or are otherwise in TRAF1 pathways may be used to indirectly modulate TRAF1 to thereby treat RA or other autoimmune/inflammatory disorders. Therapeutic agents such as these may be used in conjunction with the SNPs provided herein.

As an example, the RA-associated SNPs provided herein may be used to predict whether an individual will respond positively to TNF inhibitor therapy and/or to determine an effective dosage of this therapy. This facilitates decision making by medical practitioners, such as in deciding whether to administer this therapy to a particular individual or select another therapy that may be better suited to the individual, or to use a particular dosage, dosing schedule, or to modify other aspects of a therapeutic regimen to effectively treat the individual, for example.

In addition to medical treatment, these uses may also be applied, for example, in the context of clinical trials of a therapeutic agent (e.g., a therapeutic agent that targets TRAF1 or other TRAF protein, PHF19, or C5 for the treatment of RA or other autoimmune/inflammatory disorders), such as to include particular individuals in a clinical trial who are predicted to positively respond to the therapeutic agent based on the SNPs provided herein and/or to exclude particular individuals from a clinical trial who are predicted to not positively respond to the therapeutic agent based on the SNPs provided herein (and/or to include these particular individuals who are predicted to not positively respond to the therapeutic agent in a clinical trial for another therapeutic agent which they may benefit from). By using the SNPs provided herein to target a therapeutic agent to individuals who are more likely to positively respond to the agent, the therapeutic agent is more likely to succeed in clinical trials by showing positive efficacy and to therefore satisfy the FDA requirements for approval. Additionally, individuals who are more likely to experience toxic or other undesirable side effects may be excluded from being administered the therapeutic agent. Furthermore, by using the SNPs provided herein to determine an effective dosage or dosing frequency, for example, the therapeutic agent may be less likely to exhibit toxicity or other undesirable side effects, as well as more likely to achieve positive efficacy.

Reports, Transmission of Reports, Programmed Computers, and Business Methods

The results of a test (e.g., an individual's risk for autoimmune disease such as RA, or an individual's predicted drug responsiveness, based on assaying one or more SNPs disclosed herein, and/or an individual's allele(s)/genotype at one or more SNPs disclosed herein, etc.), and/or any other information pertaining to a test, may be referred to herein as a “report”. A tangible report can optionally be generated as part of a testing process (which may be interchangeably referred to herein as “reporting”, or as “providing” a report, “producing” a report, or “generating” a report).

Examples of tangible reports may include, but are not limited to, reports in paper (such as computer-generated printouts of test results) or equivalent formats and reports stored on computer readable medium (such as a CD, USB flash drive or other removable storage device, computer hard drive, or computer network server, etc.). Reports, particularly those stored on computer readable medium, can be part of a database, which may optionally be accessible via the internet (such as a database of patient records or genetic information stored on a computer network server, which may be a “secure database” that has security features that limit access to the report, such as to allow only the patient and the patient's medical practitioners to view the report while preventing other unauthorized individuals from viewing the report, for example). In addition to, or as an alternative to, generating a tangible report, reports can also be displayed on a computer screen (or the display of another electronic device or instrument).

A report can include, for example, an individual's risk for autoimmune disease, such as RA, or may just include the allele(s)/genotype that an individual carries at one or more SNPs disclosed herein, which may optionally be linked to information regarding the significance of having the allele(s)/genotype at the SNP (for example, a report on computer readable medium such as a network server may include hyperlink(s) to one or more journal publications or web sites that describe the medical/biological implications, such as increased or decreased disease risk, for individuals having a certain allele/genotype at the SNP). Thus, for example, the report can include disease risk or other medical/biological significance (e.g., drug responsiveness, etc.) as well as optionally also including the allele/genotype information, or the report may just include allele/genotype information without including disease risk or other medical/biological significance (such that an individual viewing the report can use the allele/genotype information to determine the associated disease risk or other medical/biological significance from a source outside of the report itself, such as from a medical practitioner, publication, website, etc., which may optionally be linked to the report such as by a hyperlink).

A report can further be “transmitted” or “communicated” (these terms may be used herein interchangeably), such as to the individual who was tested, a medical practitioner (e.g., a doctor, nurse, clinical laboratory practitioner, genetic counselor, etc.), a healthcare organization, a clinical laboratory, and/or any other party or requester intended to view or possess the report. The act of “transmitting” or “communicating” a report can be by any means known in the art, based on the format of the report. Furthermore, “transmitting” or “communicating” a report can include delivering a report (“pushing”) and/or retrieving (“pulling”) a report. For example, reports can be transmitted/communicated by various means, including being physically transferred between parties (such as for reports in paper format) such as by being physically delivered from one party to another, or by being transmitted electronically or in signal form (e.g., via e-mail or over the internet, by facsimile, and/or by any wired or wireless communication methods known in the art) such as by being retrieved from a database stored on a computer network server, etc.

In certain exemplary embodiments, the invention provides computers (or other apparatus/devices such as biomedical devices or laboratory instrumentation) programmed to carry out the methods described herein. For example, in certain embodiments, the invention provides a computer programmed to receive (i.e., as input) the identity (e.g., the allele(s) or genotype at a SNP) of one or more SNPs disclosed herein and provide (i.e., as output) the disease risk (e.g., an individual's risk for autoimmune disease such as RA) or other result (e.g., disease diagnosis or prognosis, drug responsiveness, etc.) based on the identity of the SNP(s). Such output (e.g., communication of disease risk, disease diagnosis or prognosis, drug responsiveness, etc.) may be, for example, in the form of a report on computer readable medium, printed in paper form, and/or displayed on a computer screen or other display.

In various exemplary embodiments, the invention further provides methods of doing business (with respect to methods of doing business, the terms “individual” and “customer” are used herein interchangeably). For example, exemplary methods of doing business can comprise assaying one or more SNPs disclosed herein and providing a report that includes, for example, a customer's risk for autoimmune disease such as RA (based on which allele(s)/genotype is present at the assayed SNP(s)) and/or that includes the allele(s)/genotype at the assayed SNP(s) which may optionally be linked to information (e.g., journal publications, websites, etc.) pertaining to disease risk or other biological/medical significance such as by means of a hyperlink (the report may be provided, for example, on a computer network server or other computer readable medium that is internet-accessible, and the report may be included in a secure database that allows the customer to access their report while preventing other unauthorized individuals from viewing the report), and optionally transmitting the report. Customers (or another party who is associated with the customer, such as the customer's doctor, for example) can request/order (e.g., purchase) the test online via the internet (or by phone, mail order, at an outlet/store, etc.), for example, and a kit can be sent/delivered (or otherwise provided) to the customer (or another party on behalf of the customer, such as the customer's doctor, for example) for collection of a biological sample from the customer (e.g., a buccal swab for collecting buccal cells), and the customer (or a party who collects the customer's biological sample) can submit their biological samples for assaying (e.g., to a laboratory or party associated with the laboratory such as a party that accepts the customer samples on behalf of the laboratory, a party for whom the laboratory is under the control of (e.g., the laboratory carries out the assays by request of the party or under a contract with the party, for example), and/or a party that receives at least a portion of the customer's payment for the test). The report (e.g., results of the assay including, for example, the customer's disease risk and/or allele(s)/genotype at the assayed SNP(s)) may be provided to the customer by, for example, the laboratory that assays the SNP(s) or a party associated with the laboratory (e.g., a party that receives at least a portion of the customer's payment for the assay, or a party that requests the laboratory to carry out the assays or that contracts with the laboratory for the assays to be carried out) or a doctor or other medical practitioner who is associated with (e.g., employed by or having a consulting or contracting arrangement with) the laboratory or with a party associated with the laboratory, or the report may be provided to a third party (e.g., a doctor, genetic counselor, hospital, etc.) which optionally provides the report to the customer. In further embodiments, the customer may be a doctor or other medical practitioner, or a hospital, laboratory, medical insurance organization, or other medical organization that requests/orders (e.g., purchases) tests for the purposes of having other individuals (e.g., their patients or customers) assayed for one or more SNPs disclosed herein and optionally obtaining a report of the assay results.

In certain exemplary methods of doing business, kits for collecting a biological sample from a customer (e.g., a buccal swab for collecting buccal cells) are provided (e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy, general merchandise store, or any other desirable outlet), online via the internet, by mail order, etc., whereby customers can obtain (e.g., purchase) the kits, collect their own biological samples, and submit (e.g., send/deliver via mail) their samples to a laboratory which assays the samples for one or more SNPs disclosed herein (such as to determine the customer's risk for autoimmune disease such as RA) and optionally provides a report to the customer (of the customer's disease risk based on their SNP genotype(s), for example) or provides the results of the assay to another party (e.g., a doctor, genetic counselor, hospital, etc.) which optionally provides a report to the customer (of the customer's disease risk based on their SNP genotype(s), for example).

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of the present invention that is associated with autoimmune disease (particularly RA), including the transcript sequences (SEQ ID NOS:1-16), genomic sequences (SEQ ID NOS:78-91), and protein sequences (SEQ ID NOS:17-32) of the encoded gene products (with the SNPs indicated by IUB codes in the nucleic acid sequences). In addition, Tables 1 and 2 include SNP context sequences, which generally include 100 nucleotide upstream (5′) plus 100 nucleotides downstream (3′) of each SNP position (SEQ ID NOS:33-77 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS:92-584 correspond to genomic-based context sequences disclosed in Table 2), the alternative nucleotides (alleles) at each SNP position, and additional information about the variant where relevant, such as SNP type (coding, missense, splice site, UTR, etc.), human populations in which the SNP was observed, observed allele frequencies, information about the encoded protein, etc.

Isolated Nucleic Acid Molecules

The present invention provides isolated nucleic acid molecules that contain one or more SNPs disclosed Table 1 and/or Table 2. Isolated nucleic acid molecules containing one or more SNPs disclosed in at least one of Tables 1 and 2 may be interchangeably referred to throughout the present text as “SNP-containing nucleic acid molecules.” Isolated nucleic acid molecules may optionally encode a full-length variant protein or fragment thereof. The isolated nucleic acid molecules of the present invention also include probes and primers (which are described in greater detail below in the section entitled “SNP Detection Reagents”), which may be used for assaying the disclosed SNPs, and isolated full-length genes, transcripts, cDNA molecules, and fragments thereof, which may be used for such purposes as expressing an encoded protein.

As used herein, an “isolated nucleic acid molecule” generally is one that contains a SNP of the present invention or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule containing a SNP of the present invention, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered “isolated.” Nucleic acid molecules present in non-human transgenic animals, which do not naturally occur in the animal, are also considered “isolated.” For example, recombinant DNA molecules contained in a vector are considered “isolated.” Further examples of “isolated” DNA molecules include recombinant DNA molecules maintained in heterologous host cells, and purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated SNP-containing DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprises one or more SNP positions disclosed by the present invention with flanking nucleotide sequences on either side of the SNP positions. A flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences. Preferably, the flanking sequence is up to about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side of a SNP position, or as long as the full-length gene or entire protein-coding sequence (or any portion thereof such as an exon), especially if the SNP-containing nucleic acid molecule is to be used to produce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNP flanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2 KB, 1 KB on either side of the SNP. Furthermore, in such instances the isolated nucleic acid molecule comprises exonic sequences (including protein-coding and/or non-coding exonic sequences), but may also include intronic sequences. Thus, any protein coding sequence may be either contiguous or separated by introns. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences and is of appropriate length such that it can be subjected to the specific manipulations or uses described herein such as recombinant protein expression, preparation of probes and primers for assaying the SNP position, and other uses specific to the SNP-containing nucleic acid sequences.

An isolated SNP-containing nucleic acid molecule can comprise, for example, a full-length gene or transcript, such as a gene isolated from genomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, or an mRNA transcript molecule. Polymorphic transcript sequences are referred to in Table 1 and provided in the Sequence Listing (SEQ ID NOS:1-16), and polymorphic genomic sequences are referred to in Table 2 and provided in the Sequence Listing (SEQ ID NOS:78-91). Furthermore, fragments of such full-length genes and transcripts that contain one or more SNPs disclosed herein are also encompassed by the present invention, and such fragments may be used, for example, to express any part of a protein, such as a particular functional domain or an antigenic epitope.

Thus, the present invention also encompasses fragments of the nucleic acid sequences as disclosed in Tables 1 and 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-16, genomic sequences are referred to in Table 2 as SEQ ID NOS:78-91, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:33-77, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:92-584) and their complements. The actual sequences referred to in the tables are provided in the Sequence Listing. A fragment typically comprises a contiguous nucleotide sequence at least about 8 or more nucleotides, more preferably at least about 12 or more nucleotides, and even more preferably at least about 16 or more nucleotides.

Furthermore, a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 nucleotides in length (or any other number in between). The length of the fragment will be based on its intended use. For example, the fragment can encode epitope-bearing regions of a variant peptide or regions of a variant peptide that differ from the normal/wild-type protein, or can be useful as a polynucleotide probe or primer. Such fragments can be isolated using the nucleotide sequences provided in Table 1 and/or Table 2 for the synthesis of a polynucleotide probe. A labeled probe can then be used, for example, to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in amplification reactions, such as for purposes of assaying one or more SNPs sites or for cloning specific regions of a gene.

An isolated nucleic acid molecule of the present invention further encompasses a SNP-containing polynucleotide that is the product of any one of a variety of nucleic acid amplification methods, which are used to increase the copy numbers of a polynucleotide of interest in a nucleic acid sample. Such amplification methods are well known in the art, and they include but are not limited to, polymerase chain reaction (PCR) (U.S. Pat. Nos. 4,683,195 and 4,683,202; PCR Technology: Principles and Applications for DNA Amplification, ed. H. A. Erlich, Freeman Press, NY, N.Y. (1992)), ligase chain reaction (LCR) (Wu and Wallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077 (1988)), strand displacement amplification (SDA) (U.S. Pat. Nos. 5,270,184 and 5,422,252), transcription-mediated amplification (TMA) (U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat. No. 6,027,923) and the like, and isothermal amplification methods such as nucleic acid sequence based amplification (NASBA) and self-sustained sequence replication (Guatelli et al., Proc Natl Acad Sci USA 87:1874 (1990)). Based on such methodologies, a person skilled in the art can readily design primers in any suitable regions 5′ and 3′ to a SNP disclosed herein. Such primers may be used to amplify DNA of any length so long that it contains the SNP of interest in its sequence.

As used herein, an “amplified polynucleotide” of the invention is a SNP-containing nucleic acid molecule whose amount has been increased at least two fold by any nucleic acid amplification method performed in vitro as compared to its starting amount in a test sample. In other preferred embodiments, an amplified polynucleotide is the result of at least ten fold, fifty fold, one hundred fold, one thousand fold, or even ten thousand fold increase as compared to its starting amount in a test sample. In a typical PCR amplification, a polynucleotide of interest is often amplified at least fifty thousand fold in amount over the unamplified genomic DNA, but the precise amount of amplification needed for an assay depends on the sensitivity of the subsequent detection method used.

Generally, an amplified polynucleotide is at least about 16 nucleotides in length. More typically, an amplified polynucleotide is at least about 20 nucleotides in length. In a preferred embodiment of the invention, an amplified polynucleotide is at least about 30 nucleotides in length. In a more preferred embodiment of the invention, an amplified polynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides in length. In yet another preferred embodiment of the invention, an amplified polynucleotide is at least about 100, 200, 300, 400, or 500 nucleotides in length. While the total length of an amplified polynucleotide of the invention can be as long as an exon, an intron or the entire gene where the SNP of interest resides, an amplified product is typically up to about 1,000 nucleotides in length (although certain amplification methods may generate amplified products greater than 1000 nucleotides in length). More preferably, an amplified polynucleotide is not greater than about 600-700 nucleotides in length. It is understood that irrespective of the length of an amplified polynucleotide, a SNP of interest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is at least about 201 nucleotides in length, comprises one of the transcript-based context sequences or the genomic-based context sequences shown in Tables 1 and 2. Such a product may have additional sequences on its 5′ end or 3′ end or both. In another embodiment, the amplified product is about 101 nucleotides in length, and it contains a SNP disclosed herein. Preferably, the SNP is located at the middle of the amplified product (e.g., at position 101 in an amplified product that is 201 nucleotides in length, or at position 51 in an amplified product that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplified product. However, as indicated above, the SNP of interest may be located anywhere along the length of the amplified product.

The present invention provides isolated nucleic acid molecules that comprise, consist of, or consist essentially of one or more polynucleotide sequences that contain one or more SNPs disclosed herein, complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules that consist of any of the nucleotide sequences shown in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-16, genomic sequences are referred to in Table 2 as SEQ ID NOS:78-91, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:33-77, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:92-584), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:17-32). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.

The present invention further provides nucleic acid molecules that consist essentially of any of the nucleotide sequences referred to in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-16, genomic sequences are referred to in Table 2 as SEQ ID NOS:78-91, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:33-77, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:92-584), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:17-32). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleotide residues in the final nucleic acid molecule.

The present invention further provides nucleic acid molecules that comprise any of the nucleotide sequences shown in Table 1 and/or Table 2 or a SNP-containing fragment thereof (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-16, genomic sequences are referred to in Table 2 as SEQ ID NOS:78-91, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:33-77, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:92-584), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:17-32). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleotide residues, such as residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have one to a few additional nucleotides or can comprise many more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made and isolated is provided below, and such techniques are well known to those of ordinary skill in the art. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

The isolated nucleic acid molecules can encode mature proteins plus additional amino or carboxyl-terminal amino acids or both, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life, or facilitate manipulation of a protein for assay or production. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limited to, nucleic acid molecules having a sequence encoding a peptide alone, a sequence encoding a mature peptide and additional coding sequences such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence), a sequence encoding a mature peptide with or without additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5′ and 3′ sequences such as transcribed but untranslated sequences that play a role in, for example, transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding, and/or stability of mRNA. In addition, the nucleic acid molecules may be fused to heterologous marker sequences encoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA, which may be obtained, for example, by molecular cloning or produced by chemical synthetic techniques or by a combination thereof. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000). Furthermore, isolated nucleic acid molecules, particularly SNP detection reagents such as probes and primers, can also be partially or completely in the form of one or more types of nucleic acid analogs, such as peptide nucleic acid (PNA). U.S. Pat. Nos. 5,539,082; 5,527,675; 5,623,049; and 5,714,331. The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the complementary non-coding strand (anti-sense strand). DNA, RNA, or PNA segments can be assembled, for example, from fragments of the human genome (in the case of DNA or RNA) or single nucleotides, short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic nucleic acid molecule. Nucleic acid molecules can be readily synthesized using the sequences provided herein as a reference; oligonucleotide and PNA oligomer synthesis techniques are well known in the art. See, e.g., Corey, “Peptide nucleic acids: expanding the scope of nucleic acid recognition,” Trends Biotechnol 15(6):224-9 (June 1997), and Hyrup et al., “Peptide nucleic acids (PNA): synthesis, properties and potential applications,” Bioorg Med Chem 4(1):5-23) (January 1996). Furthermore, large-scale automated oligonucleotide/PNA synthesis (including synthesis on an array or bead surface or other solid support) can readily be accomplished using commercially available nucleic acid synthesizers, such as the Applied Biosystems (Foster City, Calif.) 3900 High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid Synthesis System, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art. Such nucleic acid analogs are useful, for example, as detection reagents (e.g., primers/probes) for detecting one or more SNPs identified in Table 1 and/or Table 2. Furthermore, kits/systems (such as beads, arrays, etc.) that include these analogs are also encompassed by the present invention. For example, PNA oligomers that are based on the polymorphic sequences of the present invention are specifically contemplated. PNA oligomers are analogs of DNA in which the phosphate backbone is replaced with a peptide-like backbone. Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters 4:1081-1082 (1994); Petersen et al., Bioorganic & Medicinal Chemistry Letters 6:793-796 (1996); Kumar et al., Organic Letters 3(9):1269-1272 (2001); WO 96/04000. PNA hybridizes to complementary RNA or DNA with higher affinity and specificity than conventional oligonucleotides and oligonucleotide analogs. The properties of PNA enable novel molecular biology and biochemistry applications unachievable with traditional oligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve the binding properties and/or stability of a nucleic acid include the use of base analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263) and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, references herein to nucleic acid molecules, SNP-containing nucleic acid molecules, SNP detection reagents (e.g., probes and primers), oligonucleotides/polynucleotides include PNA oligomers and other nucleic acid analogs. Other examples of nucleic acid analogs and alternative/modified nucleic acid chemistries known in the art are described in Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules that encode fragments of the variant polypeptides disclosed herein as well as nucleic acid molecules that encode obvious variants of such variant polypeptides. Such nucleic acid molecules may be naturally occurring, such as paralogs (different locus) and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Non-naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, the variants can contain nucleotide substitutions, deletions, inversions and insertions (in addition to the SNPs disclosed in Tables 1 and 2). Variation can occur in either or both the coding and non-coding regions. The variations can produce conservative and/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1 and 2, such as naturally occurring allelic variants (as well as orthologs and paralogs) and synthetic variants produced by mutagenesis techniques, can be identified and/or produced using methods well known in the art. Such further variants can comprise a nucleotide sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence disclosed in Table 1 and/or Table 2 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Further, variants can comprise a nucleotide sequence that encodes a polypeptide that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a polypeptide sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Thus, an aspect of the present invention that is specifically contemplated are isolated nucleic acid molecules that have a certain degree of sequence variation compared with the sequences shown in Tables 1-2, but that contain a novel SNP allele disclosed herein. In other words, as long as an isolated nucleic acid molecule contains a novel SNP allele disclosed herein, other portions of the nucleic acid molecule that flank the novel SNP allele can vary to some degree from the specific transcript, genomic, and context sequences referred to and shown in Tables 1 and 2, and can encode a polypeptide that varies to some degree from the specific polypeptide sequences referred to in Table 1.

To determine the percent identity of two amino acid sequences or two nucleotide sequences of two molecules that share sequence homology, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. Computational Molecular Biology, A. M. Lesk, ed., Oxford University Press, N.Y. (1988); Biocomputing: Informatics and Genome Projects, D. W. Smith, ed., Academic Press, N.Y. (1993); Computer Analysis of Sequence Data, Part 1, A. M. Griffin and H. G. Griffin, eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology, G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence Analysis Primer, M. Gribskov and J.

Devereux, eds., M. Stockton Press, N.Y. (1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (J Mol Biol (48):444-453 (1970)) which has been incorporated into the GAP program in the GCG software package, using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. J. Devereux et al., Nucleic Acids Res. 12(1):387 (1984). In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention can further be used as a “query sequence” to perform a search against sequence databases; for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0). Altschul et al., J Mol Biol 215:403-10 (1990). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized. Altschul et al., Nucleic Acids Res 25(17):3389-3402 (1997). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. In addition to BLAST, examples of other search and sequence comparison programs used in the art include, but are not limited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994)) and KERR (Dufresne et al., Nat Biotechnol 20(12):1269-71 (December 2002)). For further information regarding bioinformatics techniques, see Current Protocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.

The present invention further provides non-coding fragments of the nucleic acid molecules disclosed in Table 1 and/or Table 2. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, intronic sequences, 5′ untranslated regions (UTRs), 3′ untranslated regions, gene modulating sequences and gene termination sequences. Such fragments are useful, for example, in controlling heterologous gene expression and in developing screens to identify gene-modulating agents.

SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed in Table 1 and/or Table 2, and their associated transcript sequences (referred to in Table 1 as SEQ ID NOS:1-16), genomic sequences (referred to in Table 2 as SEQ ID NOS:78-91), and context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:33-77; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:92-584), can be used for the design of SNP detection reagents. The actual sequences referred to in the tables are provided in the Sequence Listing. As used herein, a “SNP detection reagent” is a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined). Typically, such detection reagent hybridizes to a target SNP-containing nucleic acid molecule by complementary base-pairing in a sequence specific manner, and discriminates the target variant sequence from other nucleic acid sequences such as an art-known form in a test sample. An example of a detection reagent is a probe that hybridizes to a target nucleic acid containing one or more of the SNPs referred to in Table 1 and/or Table 2. In a preferred embodiment, such a probe can differentiate between nucleic acids having a particular nucleotide (allele) at a target SNP position from other nucleic acids that have a different nucleotide at the same target SNP position. In addition, a detection reagent may hybridize to a specific region 5′ and/or 3′ to a SNP position, particularly a region corresponding to the context sequences referred to in Table 1 and/or Table 2 (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:33-77; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:92-584). Another example of a detection reagent is a primer that acts as an initiation point of nucleotide extension along a complementary strand of a target polynucleotide. The SNP sequence information provided herein is also useful for designing primers, e.g. allele-specific primers, to amplify (e.g., using PCR) any SNP of the present invention.

In one preferred embodiment of the invention, a SNP detection reagent is an isolated or synthetic DNA or RNA polynucleotide probe or primer or PNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizes to a segment of a target nucleic acid molecule containing a SNP identified in Table 1 and/or Table 2. A detection reagent in the form of a polynucleotide may optionally contain modified base analogs, intercalators or minor groove binders. Multiple detection reagents such as probes may be, for example, affixed to a solid support (e.g., arrays or beads) or supplied in solution (e.g. probe/primer sets for enzymatic reactions such as PCR, RT-PCR, TaqMan assays, or primer-extension reactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotide or PNA oligomer. Such oligonucleotide typically comprises a region of complementary nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50, 55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) or more consecutive nucleotides in a target nucleic acid molecule. Depending on the particular assay, the consecutive nucleotides can either include the target SNP position, or be a specific region in close enough proximity 5′ and/or 3′ to the SNP position to carry out the desired assay.

Other preferred primer and probe sequences can readily be determined using the transcript sequences (SEQ ID NOS:1-16), genomic sequences (SEQ ID NOS:78-91), and SNP context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:33-77; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:92-584) disclosed in the Sequence Listing and in Tables 1 and 2. The actual sequences referred to in the tables are provided in the Sequence Listing. It will be apparent to one of skill in the art that such primers and probes are directly useful as reagents for genotyping the SNPs of the present invention, and can be incorporated into any kit/system format.

In order to produce a probe or primer specific for a target SNP-containing sequence, the gene/transcript and/or context sequence surrounding the SNP of interest is typically examined using a computer algorithm that starts at the 5′ or at the 3′ end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene/SNP context sequence, have a GC content within a range suitable for hybridization, lack predicted secondary structure that may interfere with hybridization, and/or possess other desired characteristics or that lack other undesired characteristics.

A primer or probe of the present invention is typically at least about 8 nucleotides in length.

In one embodiment of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred embodiment, a primer or a probe is at least about 12 nucleotides in length. In a more preferred embodiment, a primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length. While the maximal length of a probe can be as long as the target sequence to be detected, depending on the type of assay in which it is employed, it is typically less than about 50, 60, 65, or 70 nucleotides in length. In the case of a primer, it is typically less than about 30 nucleotides in length. In a specific preferred embodiment of the invention, a primer or a probe is within the length of about 18 and about 28 nucleotides. However, in other embodiments, such as nucleic acid arrays and other embodiments in which probes are affixed to a substrate, the probes can be longer, such as on the order of 30-70, 75, 80, 90, 100, or more nucleotides in length (see the section below entitled “SNP Detection Kits and Systems”).

For analyzing SNPs, it may be appropriate to use oligonucleotides specific for alternative SNP alleles. Such oligonucleotides that detect single nucleotide variations in target sequences may be referred to by such terms as “allele-specific oligonucleotides,” “allele-specific probes,” or “allele-specific primers.” The design and use of allele-specific probes for analyzing polymorphisms is described in, e.g., Mutation Detection: A Practical Approach, Cotton et al., eds., Oxford University Press (1998); Saiki et al., Nature 324:163-166 (1986); Dattagupta, EP235,726; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends on variables such as the precise composition of the nucleotide sequences flanking a SNP position in a target nucleic acid molecule, and the length of the primer or probe, another factor in the use of primers and probes is the stringency of the condition under which the hybridization between the probe or primer and the target sequence is performed. Higher stringency conditions utilize buffers with lower ionic strength and/or a higher reaction temperature, and tend to require a more perfect match between probe/primer and a target sequence in order to form a stable duplex. If the stringency is too high, however, hybridization may not occur at all. In contrast, lower stringency conditions utilize buffers with higher ionic strength and/or a lower reaction temperature, and permit the formation of stable duplexes with more mismatched bases between a probe/primer and a target sequence. By way of example and not limitation, exemplary conditions for high stringency hybridization conditions using an allele-specific probe are as follows: prehybridization with a solution containing 5× standard saline phosphate EDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe with target nucleic acid molecules in the same solution at the same temperature, followed by washing with a solution containing 2×SSPE, and 0.1% SDS at 55° C. or room temperature.

Moderate stringency hybridization conditions may be used for allele-specific primer extension reactions with a solution containing, e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may be carried out at an elevated temperature such as 60° C. In another embodiment, a moderately stringent hybridization condition suitable for oligonucleotide ligation assay (OLA) reactions wherein two probes are ligated if they are completely complementary to the target sequence may utilize a solution of about 100 mM KCl at a temperature of 46° C.

In a hybridization-based assay, allele-specific probes can be designed that hybridize to a segment of target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms (e.g., alternative SNP alleles/nucleotides) in the respective DNA segments from the two individuals. Hybridization conditions should be sufficiently stringent that there is a significant detectable difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles or significantly more strongly to one allele. While a probe may be designed to hybridize to a target sequence that contains a SNP site such that the SNP site aligns anywhere along the sequence of the probe, the probe is preferably designed to hybridize to a segment of the target sequence such that the SNP site aligns with a central position of the probe (e.g., a position within the probe that is at least three nucleotides from either end of the probe). This design of probe generally achieves good discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize to a segment of target DNA such that the SNP aligns with either the 5′ most end or the 3′ most end of the probe or primer. In a specific preferred embodiment that is particularly suitable for use in a oligonucleotide ligation assay (U.S. Pat. No. 4,988,617), the 3′ most nucleotide of the probe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well known in the art. Chemical synthetic methods include, but are not limited to, the phosphotriester method described by Narang et al., Methods in Enzymology 68:90 (1979); the phosphodiester method described by Brown et al., Methods in Enzymology 68:109 (1979); the diethylphosphoamidate method described by Beaucage et al., Tetrahedron Letters 22:1859 (1981); and the solid support method described in U.S. Pat. No. 4,458,066.

Allele-specific probes are often used in pairs (or, less commonly, in sets of 3 or 4, such as if a SNP position is known to have 3 or 4 alleles, respectively, or to assay both strands of a nucleic acid molecule for a target SNP allele), and such pairs may be identical except for a one nucleotide mismatch that represents the allelic variants at the SNP position. Commonly, one member of a pair perfectly matches a reference form of a target sequence that has a more common SNP allele (i.e., the allele that is more frequent in the target population) and the other member of the pair perfectly matches a form of the target sequence that has a less common SNP allele (i.e., the allele that is rarer in the target population). In the case of an array, multiple pairs of probes can be immobilized on the same support for simultaneous analysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes to a region on a target nucleic acid molecule that overlaps a SNP position and only primes amplification of an allelic form to which the primer exhibits perfect complementarity. Gibbs, Nucleic Acid Res 17:2427-2448 (1989). Typically, the primer's 3′-most nucleotide is aligned with and complementary to the SNP position of the target nucleic acid molecule. This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers, producing a detectable product that indicates which allelic form is present in the test sample. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification or substantially reduces amplification efficiency, so that either no detectable product is formed or it is formed in lower amounts or at a slower pace. The method generally works most effectively when the mismatch is at the 3′-most position of the oligonucleotide (i.e., the 3′-most position of the oligonucleotide aligns with the target SNP position) because this position is most destabilizing to elongation from the primer (see, e.g., WO 93/22456). This PCR-based assay can be utilized as part of the TaqMan assay, described below.

In a specific embodiment of the invention, a primer of the invention contains a sequence substantially complementary to a segment of a target SNP-containing nucleic acid molecule except that the primer has a mismatched nucleotide in one of the three nucleotide positions at the 3′-most end of the primer, such that the mismatched nucleotide does not base pair with a particular allele at the SNP site. In a preferred embodiment, the mismatched nucleotide in the primer is the second from the last nucleotide at the 3′-most position of the primer. In a more preferred embodiment, the mismatched nucleotide in the primer is the last nucleotide at the 3′-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of the invention is labeled with a fluorogenic reporter dye that emits a detectable signal. While the preferred reporter dye is a fluorescent dye, any reporter dye that can be attached to a detection reagent such as an oligonucleotide probe or primer is suitable for use in the invention. Such dyes include, but are not limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may be further labeled with a quencher dye such as Tamra, especially when the reagent is used as a self-quenching probe such as a TaqMan (U.S. Pat. Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos. 5,118,801 and 5,312,728), or other stemless or linear beacon probe (Livak et al., PCR Method Appl 4:357-362 (1995); Tyagi et al., Nature Biotechnology 14:303-308 (1996); Nazarenko et al., Nucl Acids Res 25:2516-2521 (1997); U.S. Pat. Nos. 5,866,336 and 6,117,635.

The detection reagents of the invention may also contain other labels, including but not limited to, biotin for streptavidin binding, hapten for antibody binding, and oligonucleotide for binding to another complementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (or that are complementary to) a SNP nucleotide identified herein but that are used to assay one or more SNPs disclosed herein. For example, primers that flank, but do not hybridize directly to a target SNP position provided herein are useful in primer extension reactions in which the primers hybridize to a region adjacent to the target SNP position (i.e., within one or more nucleotides from the target SNP site). During the primer extension reaction, a primer is typically not able to extend past a target SNP site if a particular nucleotide (allele) is present at that target SNP site, and the primer extension product can be detected in order to determine which SNP allele is present at the target SNP site. For example, particular ddNTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension product which includes a ddNTP at the 3′-most end of the primer extension product, and in which the ddNTP is a nucleotide of a SNP disclosed herein, is a composition that is specifically contemplated by the present invention). Thus, reagents that bind to a nucleic acid molecule in a region adjacent to a SNP site and that are used for assaying the SNP site, even though the bound sequences do not necessarily include the SNP site itself, are also contemplated by the present invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP and associated sequence information disclosed herein, detection reagents can be developed and used to assay any SNP of the present invention individually or in combination, and such detection reagents can be readily incorporated into one of the established kit or system formats which are well known in the art. The terms “kits” and “systems,” as used herein in the context of SNP detection reagents, are intended to refer to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, etc.). Accordingly, the present invention further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g. TaqMan probe/primer sets), arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the present invention. The kits/systems can optionally include various electronic hardware components; for example, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip” systems) provided by various manufacturers typically comprise hardware components. Other kits/systems (e.g., probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with, optionally, other biochemical reagents) packaged in one or more containers.

In some embodiments, a SNP detection kit typically contains one or more detection reagents and other components (e.g. a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger-type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like) necessary to carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule. A kit may further contain means for determining the amount of a target nucleic acid, and means for comparing the amount with a standard, and can comprise instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest. In one embodiment of the present invention, kits are provided which contain the necessary reagents to carry out one or more assays to detect one or more SNPs disclosed herein. In a preferred embodiment of the present invention, SNP detection kits/systems are in the form of nucleic acid arrays, or compartmentalized kits, including microfluidic/lab-on-a-chip systems.

SNP detection kits/systems may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele-specific probes may be included in the kit/system to simultaneously assay large numbers of SNPs, at least one of which is a SNP of the present invention. In some kits/systems, the allele-specific probes are immobilized to a substrate such as an array or bead. For example, the same substrate can comprise allele-specific probes for detecting at least 1; 10; 100; 1000; 10,000; 100,000 (or any other number in-between) or substantially all of the SNPs shown in Table 1 and/or Table 2.

The terms “arrays,” “microarrays,” and “DNA chips” are used herein interchangeably to refer to an array of distinct polynucleotides affixed to a substrate, such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support. The polynucleotides can be synthesized directly on the substrate, or synthesized separate from the substrate and then affixed to the substrate. In one embodiment, the microarray is prepared and used according to the methods described in Chee et al., U.S. Pat. No. 5,837,832 and PCT application WO95/11995; D. J. Lockhart et al., Nat Biotech 14:1675-1680 (1996); and M. Schena et al., Proc Natl Acad Sci 93:10614-10619 (1996), all of which are incorporated herein in their entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al., U.S. Pat. No. 5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteo et al., “New chips for molecular biology and diagnostics,” Biotechnol Annu Rev 8:85-101 (2002); Sosnowski et al., “Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications,” Psychiatr Genet. 12(4):181-92 (December 2002); Heller, “DNA microarray technology: devices, systems, and applications,” Annu Rev Biomed Eng 4:129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al., “Analysis of SNPs and other genomic variations using gel-based chips,” Hum Mutat 19(4):343-60 (April 2002); and McGall et al., “High-density genechip oligonucleotide probe arrays,” Adv Biochem Eng Biotechnol 77:21-42 (2002).

Any number of probes, such as allele-specific probes, may be implemented in an array, and each probe or pair of probes can hybridize to a different SNP position. In the case of polynucleotide probes, they can be synthesized at designated areas (or synthesized separately and then affixed to designated areas) on a substrate using a light-directed chemical process. Each DNA chip can contain, for example, thousands to millions of individual synthetic polynucleotide probes arranged in a grid-like pattern and miniaturized (e.g., to the size of a dime). Preferably, probes are attached to a solid support in an ordered, addressable array.

A microarray can be composed of a large number of unique, single-stranded polynucleotides, usually either synthetic antisense polynucleotides or fragments of cDNAs, fixed to a solid support. Typical polynucleotides are preferably about 6-60 nucleotides in length, more preferably about 15-30 nucleotides in length, and most preferably about 18-25 nucleotides in length. For certain types of microarrays or other detection kits/systems, it may be preferable to use oligonucleotides that are only about 7-20 nucleotides in length. In other types of arrays, such as arrays used in conjunction with chemiluminescent detection technology, preferred probe lengths can be, for example, about 15-80 nucleotides in length, preferably about 50-70 nucleotides in length, more preferably about 55-65 nucleotides in length, and most preferably about 60 nucleotides in length. The microarray or detection kit can contain polynucleotides that cover the known 5′ or 3′ sequence of a gene/transcript or target SNP site, sequential polynucleotides that cover the full-length sequence of a gene/transcript; or unique polynucleotides selected from particular areas along the length of a target gene/transcript sequence, particularly areas corresponding to one or more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides used in the microarray or detection kit can be specific to a SNP or SNPs of interest (e.g., specific to a particular SNP allele at a target SNP site, or specific to particular SNP alleles at multiple different SNP sites), or specific to a polymorphic gene/transcript or genes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on the differences in hybridization stability of the probes to perfectly matched and mismatched target sequence variants. For SNP genotyping, it is generally preferable that stringency conditions used in hybridization assays are high enough such that nucleic acid molecules that differ from one another at as little as a single SNP position can be differentiated (e.g., typical SNP hybridization assays are designed so that hybridization will occur only if one particular nucleotide is present at a SNP position, but will not occur if an alternative nucleotide is present at that SNP position). Such high stringency conditions may be preferable when using, for example, nucleic acid arrays of allele-specific probes for SNP detection. Such high stringency conditions are described in the preceding section, and are well known to those skilled in the art and can be found in, for example, Current Protocols in Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y. (1989).

In other embodiments, the arrays are used in conjunction with chemiluminescent detection technology. The following patents and patent applications, which are all hereby incorporated by reference, provide additional information pertaining to chemiluminescent detection. U.S. patent applications that describe chemiluminescent approaches for microarray detection: Ser. Nos. 10/620,332 and 10/620,333. U.S. patents that describe methods and compositions of dioxetane for performing chemiluminescent detection: U.S. Pat. Nos. 6,124,478; 6,107,024; 5,994,073; 5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. And the U.S. published application that discloses methods and compositions for microarray controls: US2002/0110828.

In one embodiment of the invention, a nucleic acid array can comprise an array of probes of about 15-25 nucleotides in length. In further embodiments, a nucleic acid array can comprise any number of probes, in which at least one probe is capable of detecting one or more SNPs disclosed in Table 1 and/or Table 2, and/or at least one probe comprises a fragment of one of the sequences selected from the group consisting of those disclosed in Table 1, Table 2, the Sequence Listing, and sequences complementary thereto, said fragment comprising at least about 8 consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, more preferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or more consecutive nucleotides (or any other number in-between) and containing (or being complementary to) a novel SNP allele disclosed in Table 1 and/or Table 2. In some embodiments, the nucleotide complementary to the SNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of the probe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application WO95/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a “gridded” array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other number which lends itself to the efficient use of commercially available instrumentation.

Using such arrays or other kits/systems, the present invention provides methods of identifying the SNPs disclosed herein in a test sample. Such methods typically involve incubating a test sample of nucleic acids with an array comprising one or more probes corresponding to at least one SNP position of the present invention, and assaying for binding of a nucleic acid from the test sample with one or more of the probes. Conditions for incubating a SNP detection reagent (or a kit/system that employs one or more such SNP detection reagents) with a test sample vary. Incubation conditions depend on such factors as the format employed in the assay, the detection methods employed, and the type and nature of the detection reagents used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification and array assay formats can readily be adapted to detect the SNPs disclosed herein.

A SNP detection kit/system of the present invention may include components that are used to prepare nucleic acids from a test sample for the subsequent amplification and/or detection of a SNP-containing nucleic acid molecule. Such sample preparation components can be used to produce nucleic acid extracts (including DNA and/or RNA), proteins or membrane extracts from any bodily fluids (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cells (especially nucleated cells) such as buccal cells (e.g., as obtained by buccal swabs), biopsies, or tissue specimens. The test samples used in the above-described methods will vary based on such factors as the assay format, nature of the detection method, and the specific tissues, cells or extracts used as the test sample to be assayed. Methods of preparing nucleic acids, proteins, and cell extracts are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized. Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, and examples are Qiagen's BioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparation system, and Roche Molecular Systems' COBAS AmpliPrep System.

Another form of kit contemplated by the present invention is a compartmentalized kit. A compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include, for example, small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allow one to efficiently transfer reagents from one compartment to another compartment such that the test samples and reagents are not cross-contaminated, or from one container to another vessel not included in the kit, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another or to another vessel. Such containers may include, for example, one or more containers which will accept the test sample, one or more containers which contain at least one probe or other SNP detection reagent for detecting one or more SNPs of the present invention, one or more containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and one or more containers which contain the reagents used to reveal the presence of the bound probe or other SNP detection reagents. The kit can optionally further comprise compartments and/or reagents for, for example, nucleic acid amplification or other enzymatic reactions such as primer extension reactions, hybridization, ligation, electrophoresis (preferably capillary electrophoresis), mass spectrometry, and/or laser-induced fluorescent detection. The kit may also include instructions for using the kit. Exemplary compartmentalized kits include microfluidic devices known in the art. See, e.g., Weigl et al., “Lab-on-a-chip for drug development,” Adv Drug Deliv Rev 55(3):349-77 (February 2003). In such microfluidic devices, the containers may be referred to as, for example, microfluidic “compartments,” “chambers,” or “channels.”

Microfluidic devices, which may also be referred to as “lab-on-a-chip” systems, biomedical micro-electro-mechanical systems (bioMEMs), or multicomponent integrated systems, are exemplary kits/systems of the present invention for analyzing SNPs. Such systems miniaturize and compartmentalize processes such as probe/target hybridization, nucleic acid amplification, and capillary electrophoresis reactions in a single functional device. Such microfluidic devices typically utilize detection reagents in at least one aspect of the system, and such detection reagents may be used to detect one or more SNPs of the present invention. One example of a microfluidic system is disclosed in U.S. Pat. No. 5,589,136, which describes the integration of PCR amplification and capillary electrophoresis in chips. Exemplary microfluidic systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples may be controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip to create functional microscopic valves and pumps with no moving parts. Varying the voltage can be used as a means to control the liquid flow at intersections between the micro-machined channels and to change the liquid flow rate for pumping across different sections of the microchip. See, for example, U.S. Pat. Nos. 6,153,073, Dubrow et al., and 6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, for example, nucleic acid amplification, primer extension, capillary electrophoresis, and a detection method such as laser induced fluorescence detection. In a first step of an exemplary process for using such an exemplary system, nucleic acid samples are amplified, preferably by PCR. Then, the amplification products are subjected to automated primer extension reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide primers to carry out primer extension reactions which hybridize just upstream of the targeted SNP. Once the extension at the 3′ end is completed, the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis. The separation medium used in capillary electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or dextran. The incorporated ddNTPs in the single nucleotide primer extension products are identified by laser-induced fluorescence detection. Such an exemplary microchip can be used to process, for example, at least 96 to 384 samples, or more, in parallel.

Uses of Nucleic Acid Molecules

The nucleic acid molecules of the present invention have a variety of uses, especially for the diagnosis, prognosis, treatment, and prevention of autoimmune disease (particularly RA), and for predicting drug response, particularly response to TNF inhibitors. For example, the nucleic acid molecules of the invention are useful for predicting an individual's risk for developing autoimmune disease (particularly the risk for RA), for prognosing the progression of autoimmune disease (e.g., the severity or consequences of RA) in an individual, in evaluating the likelihood of an individual who has autoimmune disease (or who is at increased risk for autoimmune disease) of responding to treatment (or prevention) of autoimmune disease with TNF inhibitor, and/or predicting the likelihood that the individual will experience toxicity or other undesirable side effects from the TNF inhibitor treatment, etc. For example, the nucleic acid molecules are useful as hybridization probes, such as for genotyping SNPs in messenger RNA, transcript, cDNA, genomic DNA, amplified DNA or other nucleic acid molecules, and for isolating full-length cDNA and genomic clones encoding the variant peptides disclosed in Table 1 as well as their orthologs.

A probe can hybridize to any nucleotide sequence along the entire length of a nucleic acid molecule referred to in Table 1 and/or Table 2. Preferably, a probe of the present invention hybridizes to a region of a target sequence that encompasses a SNP position indicated in Table 1 and/or Table 2. More preferably, a probe hybridizes to a SNP-containing target sequence in a sequence-specific manner such that it distinguishes the target sequence from other nucleotide sequences which vary from the target sequence only by which nucleotide is present at the SNP site. Such a probe is particularly useful for detecting the presence of a SNP-containing nucleic acid in a test sample, or for determining which nucleotide (allele) is present at a particular SNP site (i.e., genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining the presence, level, form, and/or distribution of nucleic acid expression. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes specific for the SNPs described herein can be used to assess the presence, expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in gene expression relative to normal levels. In vitro techniques for detection of mRNA include, for example, Northern blot hybridizations and in situ hybridizations. In vitro techniques for detecting DNA include Southern blot hybridizations and in situ hybridizations. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

Probes can be used as part of a diagnostic test kit for identifying cells or tissues in which a variant protein is expressed, such as by measuring the level of a variant protein-encoding nucleic acid (e.g., mRNA) in a sample of cells from a subject or determining if a polynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used as hybridization probes to detect the SNPs disclosed herein, thereby determining whether an individual with the polymorphism(s) is at risk for developing autoimmune disease (or has already developed early stage autoimmune disease), or the likelihood that an individual will respond positively to TNF inhibitor treatment (including preventive treatment) of autoimmune disease. Detection of a SNP associated with a disease phenotype provides a diagnostic tool for an active disease and/or genetic predisposition to the disease.

Furthermore, the nucleic acid molecules of the invention are therefore useful for detecting a gene (gene information is disclosed in Table 2, for example) which contains a SNP disclosed herein and/or products of such genes, such as expressed mRNA transcript molecules (transcript information is disclosed in Table 1, for example), and are thus useful for detecting gene expression. The nucleic acid molecules can optionally be implemented in, for example, an array or kit format for use in detecting gene expression.

The nucleic acid molecules of the invention are also useful as primers to amplify any given region of a nucleic acid molecule, particularly a region containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful for constructing recombinant vectors (described in greater detail below). Such vectors include expression vectors that express a portion of, or all of, any of the variant peptide sequences referred to in Table 1. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced SNPs.

The nucleic acid molecules of the invention are also useful for expressing antigenic portions of the variant proteins, particularly antigenic portions that contain a variant amino acid sequence (e.g., an amino acid substitution) caused by a SNP disclosed in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful for constructing vectors containing a gene regulatory region of the nucleic acid molecules of the present invention.

The nucleic acid molecules of the invention are also useful for designing ribozymes corresponding to all, or a part, of an mRNA molecule expressed from a SNP-containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and variant peptides.

The nucleic acid molecules of the invention are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and variant peptides. The production of recombinant cells and transgenic animals having nucleic acid molecules which contain the SNPs disclosed in Table 1 and/or Table 2 allows, for example, effective clinical design of treatment compounds and dosage regimens.

The nucleic acid molecules of the invention are also useful in assays for drug screening to identify compounds that, for example, modulate nucleic acid expression.

The nucleic acid molecules of the invention are also useful in gene therapy in patients whose cells have aberrant gene expression. Thus, recombinant cells, which include a patient's cells that have been engineered ex vivo and returned to the patient, can be introduced into an individual where the recombinant cells produce the desired protein to treat the individual.

SNP Genotyping Methods

The process of determining which nucleotide(s) is/are present at each of one or more SNP positions (such as a SNP position disclosed in Table 1 and/or Table 2), for either or both alleles, may be referred to by such phrases as SNP genotyping, determining the “identity” of a SNP, determining the “content” of a SNP, or determining which nucleotide(s)/allele(s) is/are present at a SNP position. Thus, these terms can refer to detecting a single allele (nucleotide) at a SNP position or can encompass detecting both alleles (nucleotides) at a SNP position (such as to determine the homozygous or heterozygous state of a SNP position). Furthermore, these terms may also refer to detecting an amino acid residue encoded by a SNP (such as alternative amino acid residues that are encoded by different codons created by alternative nucleotides at a missense SNP position, for example).

The present invention provides methods of SNP genotyping, such as for use in evaluating an individual's risk for developing autoimmune disease (particularly RA), for evaluating an individual's prognosis for disease severity and recovery, for predicting the likelihood that an individual who has previously had autoimmune disease (such as RA) will have a recurrence of autoimmune disease again in the future, for implementing a preventive or treatment regimen for an individual based on that individual having an increased susceptibility for developing autoimmune disease (e.g., increased risk for RA), in evaluating an individual's likelihood of responding to TNF inhibitor treatment (particularly for treating or preventing autoimmune disease), in selecting a treatment or preventive regimen (e.g., in deciding whether or not to administer TNF inhibitor treatment to an individual having autoimmune disease, or who is at increased risk for developing autoimmune disease in the future), or in formulating or selecting a particular TNF inhibitor-based treatment or preventive regimen such as dosage and/or frequency of administration of TNF inhibitor treatment or choosing which form/type of TNF inhibitor to be administered, such as a particular pharmaceutical composition or antibody, fusion protein, small molecule compound, nucleic acid agent, etc.), determining the likelihood of experiencing toxicity or other undesirable side effects from TNF inhibitor treatment, or selecting individuals for a clinical trial of a TNF inhibitor (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the TNF inhibitor treatment and/or excluding individuals from the trial who are unlikely to respond positively from the TNF inhibitor treatment based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to TNF inhibitors based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them), etc.

Nucleic acid samples can be genotyped to determine which allele(s) is/are present at any given genetic region (e.g., SNP position) of interest by methods well known in the art. The neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format. Exemplary SNP genotyping methods are described in Chen et al., “Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput,” Pharmacogenomics J 3(2):77-96 (2003); Kwok et al., “Detection of single nucleotide polymorphisms,” Curr Issues Mol Biol 5(2):43-60 (April 2003); Shi, “Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes,” Am J Pharmacogenomics 2(3):197-205 (2002); and Kwok, “Methods for genotyping single nucleotide polymorphisms,” Annu Rev Genomics Hum Genet. 2:235-58 (2001). Exemplary techniques for high-throughput SNP genotyping are described in Marnellos, “High-throughput SNP analysis for genetic association studies,” Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). Common SNP genotyping methods include, but are not limited to, TaqMan assays, molecular beacon assays, nucleic acid arrays, allele-specific primer extension, allele-specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, pyrosequencing, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length polymorphism, single base extension-tag assays, and the Invader assay. Such methods may be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.

Various methods for detecting polymorphisms include, but are not limited to, methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al., Meth. Enzymol 217:286-295 (1992)), comparison of the electrophoretic mobility of variant and wild type nucleic acid molecules (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat Res 285:125-144 (1993); and Hayashi et al., Genet Anal Tech Appl 9:73-79 (1992)), and assaying the movement of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturant using denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequence variations at specific locations can also be assessed by nuclease protection assays such as RNase and S1 protection or chemical cleavage methods.

In a preferred embodiment, SNP genotyping is performed using the TaqMan assay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos. 5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of a specific amplified product during PCR. The TaqMan assay utilizes an oligonucleotide probe labeled with a fluorescent reporter dye and a quencher dye. The reporter dye is excited by irradiation at an appropriate wavelength, it transfers energy to the quencher dye in the same probe via a process called fluorescence resonance energy transfer (FRET). When attached to the probe, the excited reporter dye does not emit a signal. The proximity of the quencher dye to the reporter dye in the intact probe maintains a reduced fluorescence for the reporter. The reporter dye and quencher dye may be at the 5′ most and the 3′ most ends, respectively, or vice versa. Alternatively, the reporter dye may be at the 5′ or 3′ most end while the quencher dye is attached to an internal nucleotide, or vice versa. In yet another embodiment, both the reporter and the quencher may be attached to internal nucleotides at a distance from each other such that fluorescence of the reporter is reduced.

During PCR, the 5′ nuclease activity of DNA polymerase cleaves the probe, thereby separating the reporter dye and the quencher dye and resulting in increased fluorescence of the reporter. Accumulation of PCR product is detected directly by monitoring the increase in fluorescence of the reporter dye. The DNA polymerase cleaves the probe between the reporter dye and the quencher dye only if the probe hybridizes to the target SNP-containing template which is amplified during PCR, and the probe is designed to hybridize to the target SNP site only if a particular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determined using the SNP and associated nucleic acid sequence information provided herein. A number of computer programs, such as Primer Express (Applied Biosystems, Foster City, Calif.), can be used to rapidly obtain optimal primer/probe sets. It will be apparent to one of skill in the art that such primers and probes for detecting the SNPs of the present invention are useful in, for example, screening for individuals who are susceptible to developing autoimmune disease (particularly RA) and related pathologies, or in screening individuals who have autoimmune disease (or who are susceptible to autoimmune disease) for their likelihood of responding to TNF inhibitor treatment. These probes and primers can be readily incorporated into a kit format. The present invention also includes modifications of the Taqman assay well known in the art such as the use of Molecular Beacon probes (U.S. Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat. Nos. 5,866,336 and 6,117,635).

Another preferred method for genotyping the SNPs of the present invention is the use of two oligonucleotide probes in an OLA (see, e.g., U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to a segment of a target nucleic acid with its 3′ most end aligned with the SNP site. A second probe hybridizes to an adjacent segment of the target nucleic acid molecule directly 3′ to the first probe. The two juxtaposed probes hybridize to the target nucleic acid molecule, and are ligated in the presence of a linking agent such as a ligase if there is perfect complementarity between the 3′ most nucleotide of the first probe with the SNP site. If there is a mismatch, ligation would not occur. After the reaction, the ligated probes are separated from the target nucleic acid molecule, and detected as indicators of the presence of a SNP.

The following patents, patent applications, and published international patent applications, which are all hereby incorporated by reference, provide additional information pertaining to techniques for carrying out various types of OLA. The following U.S. patents describe OLA strategies for performing SNP detection: U.S. Pat. Nos. 6,027,889; 6,268,148; 5,494,810; 5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describe OLA strategies for performing SNP detection using universal arrays, wherein a zipcode sequence can be introduced into one of the hybridization probes, and the resulting product, or amplified product, hybridized to a universal zip code array. U.S. application US01/17329 (and Ser. No. 09/584,905) describes OLA (or LDR) followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are determined by electrophoretic or universal zipcode array readout. U.S. applications 60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods and software for multiplexed SNP detection using OLA followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are hybridized with a zipchute reagent, and the identity of the SNP determined from electrophoretic readout of the zipchute. In some embodiments, OLA is carried out prior to PCR (or another method of nucleic acid amplification). In other embodiments, PCR (or another method of nucleic acid amplification) is carried out prior to OLA.

Another method for SNP genotyping is based on mass spectrometry. Mass spectrometry takes advantage of the unique mass of each of the four nucleotides of DNA. SNPs can be unambiguously genotyped by mass spectrometry by measuring the differences in the mass of nucleic acids having alternative SNP alleles. MALDI-TOF (Matrix Assisted Laser Desorption Ionization—Time of Flight) mass spectrometry technology is preferred for extremely precise determinations of molecular mass, such as SNPs. Numerous approaches to SNP analysis have been developed based on mass spectrometry. Preferred mass spectrometry-based methods of SNP genotyping include primer extension assays, which can also be utilized in combination with other approaches, such as traditional gel-based formats and microarrays.

Typically, the primer extension assay involves designing and annealing a primer to a template PCR amplicon upstream (5′) from a target SNP position. A mix of dideoxynucleotide triphosphates (ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to a reaction mixture containing template (e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR), primer, and DNA polymerase. Extension of the primer terminates at the first position in the template where a nucleotide complementary to one of the ddNTPs in the mix occurs. The primer can be either immediately adjacent (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide next to the target SNP site) or two or more nucleotides removed from the SNP position. If the primer is several nucleotides removed from the target SNP position, the only limitation is that the template sequence between the 3′ end of the primer and the SNP position cannot contain a nucleotide of the same type as the one to be detected, or this will cause premature termination of the extension primer. Alternatively, if all four ddNTPs alone, with no dNTPs, are added to the reaction mixture, the primer will always be extended by only one nucleotide, corresponding to the target SNP position. In this instance, primers are designed to bind one nucleotide upstream from the SNP position (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide that is immediately adjacent to the target SNP site on the 5′ side of the target SNP site). Extension by only one nucleotide is preferable, as it minimizes the overall mass of the extended primer, thereby increasing the resolution of mass differences between alternative SNP nucleotides. Furthermore, mass-tagged ddNTPs can be employed in the primer extension reactions in place of unmodified ddNTPs. This increases the mass difference between primers extended with these ddNTPs, thereby providing increased sensitivity and accuracy, and is particularly useful for typing heterozygous base positions. Mass-tagging also alleviates the need for intensive sample-preparation procedures and decreases the necessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF mass spectrometry to determine the identity of the nucleotide present at the target SNP position. In one method of analysis, the products from the primer extension reaction are combined with light absorbing crystals that form a matrix. The matrix is then hit with an energy source such as a laser to ionize and desorb the nucleic acid molecules into the gas-phase. The ionized molecules are then ejected into a flight tube and accelerated down the tube towards a detector. The time between the ionization event, such as a laser pulse, and collision of the molecule with the detector is the time of flight of that molecule. The time of flight is precisely correlated with the mass-to-charge ratio (m/z) of the ionized molecule. Ions with smaller m/z travel down the tube faster than ions with larger m/z and therefore the lighter ions reach the detector before the heavier ions. The time-of-flight is then converted into a corresponding, and highly precise, m/z. In this manner, SNPs can be identified based on the slight differences in mass, and the corresponding time of flight differences, inherent in nucleic acid molecules having different nucleotides at a single base position. For further information regarding the use of primer extension assays in conjunction with MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise et al., “A standard protocol for single nucleotide primer extension in the human genome using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,” Rapid Commun Mass Spectrom 17(11):1195-202 (2003).

The following references provide further information describing mass spectrometry-based methods for SNP genotyping: Bocker, “SNP and mutation discovery using base-specific cleavage and MALDI-TOF mass spectrometry,” Bioinformatics 19 Suppl 1:I44-I53 (July 2003); Storm et al., “MALDI-TOF mass spectrometry-based SNP genotyping,” Methods Mol Biol 212:241-62 (2003); Jurinke et al., “The use of Mass ARRAY technology for high throughput genotyping,” Adv Biochem Eng Biotechnol 77:57-74 (2002); and Jurinke et al., “Automated genotyping using the DNA MassArray technology,” Methods Mol Biol 187:179-92 (2002).

SNPs can also be scored by direct DNA sequencing. A variety of automated sequencing procedures can be utilized (e.g. Biotechniques 19:448 (1995)), including sequencing by mass spectrometry. See, e.g., PCT International Publication No. WO 94/16101; Cohen et al., Adv Chromatogr 36:127-162 (1996); and Griffin et al., Appl Biochem Biotechnol 38:147-159 (1993). The nucleic acid sequences of the present invention enable one of ordinary skill in the art to readily design sequencing primers for such automated sequencing procedures. Commercial instrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730×1 DNA Analyzers (Foster City, Calif.), is commonly used in the art for automated sequencing.

Other methods that can be used to genotype the SNPs of the present invention include single-strand conformational polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE). Myers et al., Nature 313:495 (1985). SSCP identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al., Proc. Nat. Acad. Single-stranded PCR products can be generated by heating or otherwise denaturing double stranded PCR products. Single-stranded nucleic acids may refold or form secondary structures that are partially dependent on the base sequence. The different electrophoretic mobilities of single-stranded amplification products are related to base-sequence differences at SNP positions. DGGE differentiates SNP alleles based on the different sequence-dependent stabilities and melting properties inherent in polymorphic DNA and the corresponding differences in electrophoretic migration patterns in a denaturing gradient gel. PCR Technology: Principles and Applications for DNA Amplification Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y. (1992).

Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be used to score SNPs based on the development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature. If the SNP affects a restriction enzyme cleavage site, the SNP can be identified by alterations in restriction enzyme digestion patterns, and the corresponding changes in nucleic acid fragment lengths determined by gel electrophoresis.

SNP genotyping can include the steps of, for example, collecting a biological sample from a human subject (e.g., sample of tissues, cells, fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product (assays can be designed so that hybridization and/or amplification will only occur if a particular SNP allele is present or absent). In some assays, the size of the amplification product is detected and compared to the length of a control sample; for example, deletions and insertions can be detected by a change in size of the amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, as described below. Examples of such applications include, but are not limited to, SNP-disease association analysis, disease predisposition screening, disease diagnosis, disease prognosis, disease progression monitoring, determining therapeutic strategies based on an individual's genotype (“pharmacogenomics”), developing therapeutic agents based on SNP genotypes associated with a disease or likelihood of responding to a drug, stratifying patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent, predicting the likelihood that an individual will experience toxic side effects from a therapeutic agent, and human identification applications such as forensics.

Analysis of Genetic Associations between SNPs and Phenotypic Traits

SNP genotyping for disease diagnosis, disease predisposition screening, disease prognosis, determining drug responsiveness (pharmacogenomics), drug toxicity screening, and other uses described herein, typically relies on initially establishing a genetic association between one or more specific SNPs and the particular phenotypic traits of interest.

Different study designs may be used for genetic association studies. Modern Epidemiology 609-622, Lippincott, Williams & Wilkins (1998). Observational studies are most frequently carried out in which the response of the patients is not interfered with. The first type of observational study identifies a sample of persons in whom the suspected cause of the disease is present and another sample of persons in whom the suspected cause is absent, and then the frequency of development of disease in the two samples is compared. These sampled populations are called cohorts, and the study is a prospective study. The other type of observational study is case-control or a retrospective study. In typical case-control studies, samples are collected from individuals with the phenotype of interest (cases) such as certain manifestations of a disease, and from individuals without the phenotype (controls) in a population (target population) that conclusions are to be drawn from. Then the possible causes of the disease are investigated retrospectively. As the time and costs of collecting samples in case-control studies are considerably less than those for prospective studies, case-control studies are the more commonly used study design in genetic association studies, at least during the exploration and discovery stage.

In both types of observational studies, there may be potential confounding factors that should be taken into consideration. Confounding factors are those that are associated with both the real cause(s) of the disease and the disease itself, and they include demographic information such as age, gender, ethnicity as well as environmental factors. When confounding factors are not matched in cases and controls in a study, and are not controlled properly, spurious association results can arise. If potential confounding factors are identified, they should be controlled for by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is a certain allele or a SNP or a combination of alleles or a haplotype from several SNPs. Thus, tissue specimens (e.g., whole blood) from the sampled individuals may be collected and genomic DNA genotyped for the SNP(s) of interest. In addition to the phenotypic trait of interest, other information such as demographic (e.g., age, gender, ethnicity, etc.), clinical, and environmental information that may influence the outcome of the trait can be collected to further characterize and define the sample set. In many cases, these factors are known to be associated with diseases and/or SNP allele frequencies. There are likely gene-environment and/or gene-gene interactions as well. Analysis methods to address gene-environment and gene-gene interactions (for example, the effects of the presence of both susceptibility alleles at two different genes can be greater than the effects of the individual alleles at two genes combined) are discussed below.

After all the relevant phenotypic and genotypic information has been obtained, statistical analyses are carried out to determine if there is any significant correlation between the presence of an allele or a genotype with the phenotypic characteristics of an individual. Preferably, data inspection and cleaning are first performed before carrying out statistical tests for genetic association. Epidemiological and clinical data of the samples can be summarized by descriptive statistics with tables and graphs. Data validation is preferably performed to check for data completion, inconsistent entries, and outliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests if distributions are not normal) may then be used to check for significant differences between cases and controls for discrete and continuous variables, respectively. To ensure genotyping quality, Hardy-Weinberg disequilibrium tests can be performed on cases and controls separately. Significant deviation from Hardy-Weinberg equilibrium (HWE) in both cases and controls for individual markers can be indicative of genotyping errors. If HWE is violated in a majority of markers, it is indicative of population substructure that should be further investigated. Moreover, Hardy-Weinberg disequilibrium in cases only can indicate genetic association of the markers with the disease. B. Weir, Genetic Data Analysis, Sinauer (1990).

To test whether an allele of a single SNP is associated with the case or control status of a phenotypic trait, one skilled in the art can compare allele frequencies in cases and controls. Standard chi-squared tests and Fisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2 outcomes in the categorical trait of interest). To test whether genotypes of a SNP are associated, chi-squared tests can be carried out on a 3×2 table (3 genotypes×2 outcomes). Score tests are also carried out for genotypic association to contrast the three genotypic frequencies (major homozygotes, heterozygotes and minor homozygotes) in cases and controls, and to look for trends using 3 different modes of inheritance, namely dominant (with contrast coefficients 2, −1, −1), additive or allelic (with contrast coefficients 1, 0, −1) and recessive (with contrast coefficients 1, 1, −2). Odds ratios for minor versus major alleles, and odds ratios for heterozygote and homozygote variants versus the wild type genotypes are calculated with the desired confidence limits, usually 95%.

In order to control for confounders and to test for interaction and effect modifiers, stratified analyses may be performed using stratified factors that are likely to be confounding, including demographic information such as age, ethnicity, and gender, or an interacting element or effect modifier, such as a known major gene (e.g., APOE for Alzheimer's disease or HLA genes for autoimmune diseases), or environmental factors such as smoking in lung cancer. Stratified association tests may be carried out using Cochran-Mantel-Haenszel tests that take into account the ordinal nature of genotypes with 0, 1, and 2 variant alleles. Exact tests by StatXact may also be performed when computationally possible. Another way to adjust for confounding effects and test for interactions is to perform stepwise multiple logistic regression analysis using statistical packages such as SAS or R. Logistic regression is a model-building technique in which the best fitting and most parsimonious model is built to describe the relation between the dichotomous outcome (for instance, getting a certain disease or not) and a set of independent variables (for instance, genotypes of different associated genes, and the associated demographic and environmental factors). The most common model is one in which the logit transformation of the odds ratios is expressed as a linear combination of the variables (main effects) and their cross-product terms (interactions). Hosmer and Lemeshow, Applied Logistic Regression, Wiley (2000). To test whether a certain variable or interaction is significantly associated with the outcome, coefficients in the model are first estimated and then tested for statistical significance of their departure from zero.

In addition to performing association tests one marker at a time, haplotype association analysis may also be performed to study a number of markers that are closely linked together.

Haplotype association tests can have better power than genotypic or allelic association tests when the tested markers are not the disease-causing mutations themselves but are in linkage disequilibrium with such mutations. The test will even be more powerful if the disease is indeed caused by a combination of alleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs that are very close to each other). In order to perform haplotype association effectively, marker-marker linkage disequilibrium measures, both D′ and r², are typically calculated for the markers within a gene to elucidate the haplotype structure. Recent studies in linkage disequilibrium indicate that SNPs within a gene are organized in block pattern, and a high degree of linkage disequilibrium exists within blocks and very little linkage disequilibrium exists between blocks. Daly et al, Nature Genetics 29:232-235 (2001). Haplotype association with the disease status can be performed using such blocks once they have been elucidated.

Haplotype association tests can be carried out in a similar fashion as the allelic and genotypic association tests. Each haplotype in a gene is analogous to an allele in a multi-allelic marker. One skilled in the art can either compare the haplotype frequencies in cases and controls or test genetic association with different pairs of haplotypes. It has been proposed that score tests can be done on haplotypes using the program “haplo.score.” Schaid et al, Am J Hum Genet. 70:425-434 (2002). In that method, haplotypes are first inferred by EM algorithm and score tests are carried out with a generalized linear model (GLM) framework that allows the adjustment of other factors.

An important decision in the performance of genetic association tests is the determination of the significance level at which significant association can be declared when the P value of the tests reaches that level. In an exploratory analysis where positive hits will be followed up in subsequent confirmatory testing, an unadjusted P value <0.2 (a significance level on the lenient side), for example, may be used for generating hypotheses for significant association of a SNP with certain phenotypic characteristics of a disease. It is preferred that a p-value <0.05 (a significance level traditionally used in the art) is achieved in order for a SNP to be considered to have an association with a disease. It is more preferred that a p-value <0.01 (a significance level on the stringent side) is achieved for an association to be declared. When hits are followed up in confirmatory analyses in more samples of the same source or in different samples from different sources, adjustment for multiple testing will be performed as to avoid excess number of hits while maintaining the experiment-wide error rates at 0.05. While there are different methods to adjust for multiple testing to control for different kinds of error rates, a commonly used but rather conservative method is Bonferroni correction to control the experiment-wise or family-wise error rate. Westfall et al., Multiple comparisons and multiple tests, SAS Institute (1999). Permutation tests to control for the false discovery rates, FDR, can be more powerful. Benjamini and Hochberg, Journal of the Royal Statistical Society, Series B 57:1289-1300 (1995); Westfall and Young, Resampling-based Multiple Testing, Wiley (1993). Such methods to control for multiplicity would be preferred when the tests are dependent and controlling for false discovery rates is sufficient as opposed to controlling for the experiment-wise error rates.

In replication studies using samples from different populations after statistically significant markers have been identified in the exploratory stage, meta-analyses can then be performed by combining evidence of different studies. Modern Epidemiology 643-673, Lippincott, Williams & Wilkins (1998). If available, association results known in the art for the same SNPs can be included in the meta-analyses.

Since both genotyping and disease status classification can involve errors, sensitivity analyses may be performed to see how odds ratios and p-values would change upon various estimates on genotyping and disease classification error rates.

It has been well known that subpopulation-based sampling bias between cases and controls can lead to spurious results in case-control association studies when prevalence of the disease is associated with different subpopulation groups. Ewens and Spielman, Am J Hum Genet. 62:450-458 (1995). Such bias can also lead to a loss of statistical power in genetic association studies. To detect population stratification, Pritchard and Rosenberg suggested typing markers that are unlinked to the disease and using results of association tests on those markers to determine whether there is any population stratification. Pritchard et al., Am J Hum Gen 65:220-228 (1999). When stratification is detected, the genomic control (GC) method as proposed by Devlin and Roeder can be used to adjust for the inflation of test statistics due to population stratification. Devlin et al., Biometrics 55:997-1004 (1999). The GC method is robust to changes in population structure levels as well as being applicable to DNA pooling designs. Devlin et al., Genet Epidem 21:273-284 (2001).

While Pritchard's method recommended using 15-20 unlinked microsatellite markers, it suggested using more than 30 biallelic markers to get enough power to detect population stratification. For the GC method, it has been shown that about 60-70 biallelic markers are sufficient to estimate the inflation factor for the test statistics due to population stratification. Bacanu et al., Am J Hum Genet. 66:1933-1944 (2000). Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicated in a genome scan. Kehoe et al., Hum Mol Genet. 8:237-245 (1999).

Once individual risk factors, genetic or non-genetic, have been found for the predisposition to disease, the next step is to set up a classification/prediction scheme to predict the category (for instance, disease or no-disease) that an individual will be in depending on his genotypes of associated SNPs and other non-genetic risk factors. Logistic regression for discrete trait and linear regression for continuous trait are standard techniques for such tasks. Draper and Smith, Applied Regression Analysis, Wiley (1998). Moreover, other techniques can also be used for setting up classification. Such techniques include, but are not limited to, MART, CART, neural network, and discriminant analyses that are suitable for use in comparing the performance of different methods. The Elements of Statistical Learning, Hastie, Tibshirani & Friedman, Springer (2002).

Disease Diagnosis and Predisposition Screening

Information on association/correlation between genotypes and disease-related phenotypes can be exploited in several ways. For example, in the case of a highly statistically significant association between one or more SNPs with predisposition to a disease for which treatment is available, detection of such a genotype pattern in an individual may justify immediate administration of treatment, or at least the institution of regular monitoring of the individual. Detection of the susceptibility alleles associated with serious disease in a couple contemplating having children may also be valuable to the couple in their reproductive decisions. In the case of a weaker but still statistically significant association between a SNP and a human disease, immediate therapeutic intervention or monitoring may not be justified after detecting the susceptibility allele or SNP. Nevertheless, the subject can be motivated to begin simple life-style changes (e.g., diet, exercise) that can be accomplished at little or no cost to the individual but would confer potential benefits in reducing the risk of developing conditions for which that individual may have an increased risk by virtue of having the risk allele(s).

The SNPs of the invention may contribute to the development of autoimmune disease (e.g., RA), or to responsiveness of an individual to TNF inhibitor treatment, in different ways. Some polymorphisms occur within a protein coding sequence and contribute to disease phenotype by affecting protein structure. Other polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on, for example, replication, transcription, and/or translation. A single SNP may affect more than one phenotypic trait. Likewise, a single phenotypic trait may be affected by multiple SNPs in different genes.

As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics” include, but are not limited to, any of the following: detection of autoimmune disease (such as RA) that an individual may presently have, predisposition/susceptibility/predictive screening (i.e., determining whether an individual has an increased or decreased risk of developing autoimmune disease in the future), prognosing the future course of autoimmune disease or recurrence of autoimmune disease in an individual, determining a particular type or subclass of autoimmune disease in an individual who currently or previously had autoimmune disease, confirming or reinforcing a previously made diagnosis of autoimmune disease, evaluating an individual's likelihood of responding positively to a particular treatment or therapeutic agent such as TNF inhibitor treatment (particularly treatment or prevention of autoimmune disease using TNF inhibitors), determining or selecting a therapeutic or preventive strategy that an individual is most likely to positively respond to (e.g., selecting a particular therapeutic agent such as a TNF inhibitor, or combination of therapeutic agents, or determining a dosing regimen, etc.), classifying (or confirming/reinforcing) an individual as a responder/non-responder (or determining a particular subtype of responder/non-responder) with respect to the individual's response to a drug treatment such as TNF inhibitor treatment, and predicting whether a patient is likely to experience toxic effects from a particular treatment or therapeutic compound. Such diagnostic uses can be based on the SNPs individually or in a unique combination or SNP haplotypes of the present invention.

Haplotypes are particularly useful in that, for example, fewer SNPs can be genotyped to determine if a particular genomic region harbors a locus that influences a particular phenotype, such as in linkage disequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles (e.g., alternative nucleotides) at two or more different SNP sites at frequencies greater than would be expected from the separate frequencies of occurrence of each allele in a given population. The expected frequency of co-occurrence of two alleles that are inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur at expected frequencies are said to be in “linkage equilibrium.” In contrast, LD refers to any non-random genetic association between allele(s) at two or more different SNP sites, which is generally due to the physical proximity of the two loci along a chromosome. LD can occur when two or more SNPs sites are in close physical proximity to each other on a given chromosome and therefore alleles at these SNP sites will tend to remain unseparated for multiple generations with the consequence that a particular nucleotide (allele) at one SNP site will show a non-random association with a particular nucleotide (allele) at a different SNP site located nearby. Hence, genotyping one of the SNP sites will give almost the same information as genotyping the other SNP site that is in LD.

Various degrees of LD can be encountered between two or more SNPs with the result being that some SNPs are more closely associated (i.e., in stronger LD) than others. Furthermore, the physical distance over which LD extends along a chromosome differs between different regions of the genome, and therefore the degree of physical separation between two or more SNP sites necessary for LD to occur can differ between different regions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site is found to be useful for, for example, predicting an individual's susceptibility to autoimmune disease or an individual's response to TNF inhibitor treatment, then the skilled artisan would recognize that other SNP sites which are in LD with this SNP site would also be useful for the same purposes. Thus, polymorphisms (e.g., SNPs and/or haplotypes) that are not the actual disease-causing (causative) polymorphisms, but are in LD with such causative polymorphisms, are also useful. In such instances, the genotype of the polymorphism(s) that is/are in LD with the causative polymorphism is predictive of the genotype of the causative polymorphism and, consequently, predictive of the phenotype (e.g., autoimmune disease, or responder/non-responder to a drug treatment) that is influenced by the causative SNP(s). Therefore, polymorphic markers that are in LD with causative polymorphisms are useful as diagnostic markers, and are particularly useful when the actual causative polymorphism(s) is/are unknown.

Examples of polymorphisms that can be in LD with one or more causative polymorphisms (and/or in LD with one or more polymorphisms that have a significant statistical association with a condition) and therefore useful for diagnosing the same condition that the causative/associated SNP(s) is used to diagnose, include other SNPs in the same gene, protein-coding, or mRNA transcript-coding region as the causative/associated SNP, other SNPs in the same exon or same intron as the causative/associated SNP, other SNPs in the same haplotype block as the causative/associated SNP, other SNPs in the same intergenic region as the causative/associated SNP, SNPs that are outside but near a gene (e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) that harbors a causative/associated SNP, etc. Such useful LD SNPs can be selected from among the SNPs disclosed in Tables 1 and 2, for example.

Linkage disequilibrium in the human genome is reviewed in Wall et al., “Haplotype blocks and linkage disequilibrium in the human genome,” Nat Rev Genet. 4(8):587-97 (August 2003); Garner et al., “On selecting markers for association studies: patterns of linkage disequilibrium between two and three diallelic loci,” Genet Epidemiol 24(1):57-67 (January 2003); Ardlie et al., “Patterns of linkage disequilibrium in the human genome,” Nat Rev Genet. 3(4):299-309 (April 2002); erratum in Nat Rev Genet. 3(7):566 (July 2002); and Remm et al., “High-density genotyping and linkage disequilibrium in the human genome using chromosome 22 as a model,” Curr Opin Chem Biol 6(1):24-30 (Feb. 2002); J. B. S. Haldane, “The combination of linkage values, and the calculation of distances between the loci of linked factors,” J Genet. 8:299-309 (1919); G. Mendel, Versuche über Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereines in Brunn (Proceedings of the Natural History Society of Brünn) (1866); Genes IV, B. Lewin, ed., Oxford University Press, N.Y. (1990); D. L. Hartl and A. G. Clark Principles of Population Genetics 2^(nd) ed., Sinauer Associates, Inc., Mass. (1989); J. H. Gillespie Population Genetics: A Concise Guide. 2^(nd) ed., Johns Hopkins University Press (2004); R. C. Lewontin, “The interaction of selection and linkage. I. General considerations; heterotic models,” Genetics 49:49-67 (1964); P. G. Hoel, Introduction to Mathematical Statistics 2^(nd) ed., John Wiley & Sons, Inc., N.Y. (1954); R. R. Hudson, “Two-locus sampling distributions and their application,” Genetics 159:1805-1817 (2001); A. P. Dempster, N. M. Laird, D. B. Rubin, “Maximum likelihood from incomplete data via the EM algorithm,” J R Stat Soc 39:1-38 (1977); L. Excoffier, M. Slatkin, “Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population,” Mol Biol Evol 12(5):921-927 (1995); D. A. Tregouet, S. Escolano, L. Tiret, A. Mallet, J. L. Golmard, “A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm,” Ann Hum Genet. 68(Pt 2):165-177 (2004); A. D. Long and C. H. Langley C H, “The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits,” Genome Research 9:720-731 (1999); A. Agresti, Categorical Data Analysis, John Wiley & Sons, Inc., N.Y. (1990); K. Lange, Mathematical and Statistical Methods for Genetic Analysis, Springer-Verlag New York, Inc., N.Y. (1997); The International HapMap Consortium, “The International HapMap Project,” Nature 426:789-796 (2003); The International HapMap Consortium, “A haplotype map of the human genome,” Nature 437:1299-1320 (2005); G. A. Thorisson, A. V. Smith, L. Krishnan, L. D. Stein, “The International HapMap Project Web Site,” Genome Research 15:1591-1593 (2005); G. McVean, C. C. A. Spencer, R. Chaix, “Perspectives on human genetic variation from the HapMap project,” PLoS Genetics 1(4):413-418 (2005); J. N. Hirschhorn, M. J. Daly, “Genome-wide association studies for common diseases and complex traits,” Nat Genet. 6:95-108 (2005); S. J. Schrodi, “A probabilistic approach to large-scale association scans: a semi-Bayesian method to detect disease-predisposing alleles,” SAGMB 4(1):31 (2005); W. Y. S. Wang, B. J. Barratt, D. G. Clayton, J. A. Todd, “Genome-wide association studies: theoretical and practical concerns,” Nat Rev Genet. 6:109-118 (2005); J. K. Pritchard, M. Przeworski, “Linkage disequilibrium in humans: models and data,” Am J Hum Genet. 69:1-14 (2001).

As discussed above, one aspect of the present invention is the discovery that SNPs that are in certain LD distance with an interrogated SNP can also be used as valid markers for determining whether an individual has an increased or decreased risk of having or developing autoimmune disease, or an individual's likelihood of benefiting from a drug treatment such as TNF inhibitor treatment. As used herein, the term “interrogated SNP” refers to SNPs that have been found to be associated with an increased or decreased risk of disease using genotyping results and analysis, or other appropriate experimental method as exemplified in the working examples described in this application. As used herein, the term “LD SNP” refers to a SNP that has been characterized as a SNP associating with an increased or decreased risk of diseases due to their being in LD with the “interrogated SNP” under the methods of calculation described in the application. Below, applicants describe the methods of calculation with which one of ordinary skilled in the art may determine if a particular SNP is in LD with an interrogated SNP. The parameter r² is commonly used in the genetics art to characterize the extent of linkage disequilibrium between markers (Hudson, 2001). As used herein, the term “in LD with” refers to a particular SNP that is measured at above the threshold of a parameter such as r² with an interrogated SNP.

It is now common place to directly observe genetic variants in a sample of chromosomes obtained from a population. Suppose one has genotype data at two genetic markers located on the same chromosome, for the markers A and B. Further suppose that two alleles segregate at each of these two markers such that alleles A₁ and A₂ can be found at marker A and alleles B₁ and B₂ at marker B. Also assume that these two markers are on a human autosome. If one is to examine a specific individual and find that they are heterozygous at both markers, such that their two-marker genotype is A₁A₂B₁B₂, then there are two possible configurations: the individual in question could have the alleles A₁B₁ on one chromosome and A₂B₂ on the remaining chromosome; alternatively, the individual could have alleles A₁B₂ on one chromosome and A₂B₁ on the other. The arrangement of alleles on a chromosome is called a haplotype. In this illustration, the individual could have haplotypes A₁B₁/A₂B₂ or A₁B₂/A₂B₁ (see Hartl and Clark (1989) for a more complete description). The concept of linkage equilibrium relates the frequency of haplotypes to the allele frequencies.

Assume that a sample of individuals is selected from a larger population. Considering the two markers described above, each having two alleles, there are four possible haplotypes: A₁B₁, A₁B₂, A₂B₁ and A₂B₂. Denote the frequencies of these four haplotypes with the following notation.

P ₁₁=freq(A ₁ B ₁)  (1)

P ₁₂=freq(A ₁ B ₂)  (2)

P ₂₁=freq(A ₂ B ₁)  (3)

P ₂₂=freq(A ₂ B ₂)  (4)

The allele frequencies at the two markers are then the sum of different haplotype frequencies, it is straightforward to write down a similar set of equations relating single-marker allele frequencies to two-marker haplotype frequencies:

p ₁=freq(A ₁)=P ₁₁ +P ₁₂  (5)

p ₂=freq(A ₂)=P ₂₁ +P ₂₂  (6)

q ₁=freq(B ₁)=P ₁₁ +P ₂₁  (7)

q ₂=freq(B ₂)=P ₁₂ +P ₂₂  (8)

Note that the four haplotype frequencies and the allele frequencies at each marker must sum to a frequency of 1.

P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1  (9)

p ₁ +p ₂=1  (10)

q ₁ +q ₂=1  (11)

If there is no correlation between the alleles at the two markers, one would expect that the frequency of the haplotypes would be approximately the product of the composite alleles. Therefore,

P ₁₁ ≈p ₁ q ₁  (12)

P ₁₂ ≈p ₁ q ₂  (13)

P ₂₁ ≈p ₂ q ₁  (14)

P ₂₂ ≈p ₂ q ₂  (15)

These approximating equations (12)-(15) represent the concept of linkage equilibrium where there is independent assortment between the two markers—the alleles at the two markers occur together at random. These are represented as approximations because linkage equilibrium and linkage disequilibrium are concepts typically thought of as properties of a sample of chromosomes; and as such they are susceptible to stochastic fluctuations due to the sampling process. Empirically, many pairs of genetic markers will be in linkage equilibrium, but certainly not all pairs.

Having established the concept of linkage equilibrium above, applicants can now describe the concept of linkage disequilibrium (LD), which is the deviation from linkage equilibrium. Since the frequency of the A₁B₁ haplotype is approximately the product of the allele frequencies for A₁ and B₁ under the assumption of linkage equilibrium as stated mathematically in (12), a simple measure for the amount of departure from linkage equilibrium is the difference in these two quantities, D,

D=P ₁₁ −p ₁ q ₁  (16)

D=0 indicates perfect linkage equilibrium. Substantial departures from D=0 indicates LD in the sample of chromosomes examined. Many properties of D are discussed in Lewontin (1964) including the maximum and minimum values that D can take. Mathematically, using basic algebra, it can be shown that D can also be written solely in terms of haplotypes:

D=P ₁₁ P ₂₂ −P ₁₂ P ₂₁  (17)

If one transforms D by squaring it and subsequently dividing by the product of the allele frequencies of A₁, A₂, B₁ and B₂, the resulting quantity, called r², is equivalent to the square of the Pearson's correlation coefficient commonly used in statistics (e.g., Hoel, 1954).

$\begin{matrix} {r^{2} = \frac{D^{2}}{p_{1}p_{2}q_{1}q_{2}}} & (18) \end{matrix}$

As with D, values of r² close to 0 indicate linkage equilibrium between the two markers examined in the sample set. As values of r² increase, the two markers are said to be in linkage disequilibrium. The range of values that r² can take are from 0 to 1. r²=1 when there is a perfect correlation between the alleles at the two markers.

In addition, the quantities discussed above are sample-specific. And as such, it is necessary to formulate notation specific to the samples studied. In the approach discussed here, three types of samples are of primary interest: (i) a sample of chromosomes from individuals affected by a disease-related phenotype (cases), (ii) a sample of chromosomes obtained from individuals not affected by the disease-related phenotype (controls), and (iii) a standard sample set used for the construction of haplotypes and calculation pairwise linkage disequilibrium. For the allele frequencies used in the development of the method described below, an additional subscript will be added to denote either the case or control sample sets.

p _(1,cs)=freq(A ₁ in cases)  (19)

p _(2,cs)=freq(A ₂ in cases)  (20)

q _(1,cs)=freq(B ₁ in cases)  (21)

q _(2,cs)=freq(B ₂ in cases)  (22)

Similarly,

p _(1,ct)=freq(A ₁ in controls)  (23)

p _(2,ct)=freq(A ₂ in controls)  (24)

q _(1,ct)=freq(B ₁ in controls)  (25)

q _(2,ct)=freq(B ₂ in controls)  (26)

As a well-accepted sample set is necessary for robust linkage disequilibrium calculations, data obtained from the International HapMap project (The International HapMap Consortium 2003, 2005; Thorisson et al, 2005; McVean et al, 2005) can be used for the calculation of pairwise r² values. Indeed, the samples genotyped for the International HapMap Project were selected to be representative examples from various human sub-populations with sufficient numbers of chromosomes examined to draw meaningful and robust conclusions from the patterns of genetic variation observed. The International HapMap project website (hapmap.org) contains a description of the project, methods utilized and samples examined. It is useful to examine empirical data to get a sense of the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above. However, knowing the 2-marker haplotype frequencies requires that phase to be determined for doubly heterozygous samples. When phase is unknown in the data examined, various algorithms can be used to infer phase from the genotype data. This issue was discussed earlier where the doubly heterozygous individual with a 2-SNP genotype of A₁A₂B₁B₂ could have one of two different sets of chromosomes: A₁B₁/A₂B₂ or A₁B₂/A₂B₁. One such algorithm to estimate haplotype frequencies is the expectation-maximization (EM) algorithm first formalized by Dempster et al. (1977). This algorithm is often used in genetics to infer haplotype frequencies from genotype data (e.g. Excoffier and Slatkin (1995); Tregouet et al. (2004)). It should be noted that for the two-SNP case explored here, EM algorithms have very little error provided that the allele frequencies and sample sizes are not too small. The impact on r² values is typically negligible.

As correlated genetic markers share information, interrogation of SNP markers in LD with a disease-associated SNP marker can also have sufficient power to detect disease association (Long and Langley (1999)). The relationship between the power to directly find disease-associated alleles and the power to indirectly detect disease-association was investigated by Pritchard and Przeworski (2001). In a straight-forward derivation, it can be shown that the power to detect disease association indirectly at a marker locus in linkage disequilibrium with a disease-association locus is approximately the same as the power to detect disease-association directly at the disease-association locus if the sample size is increased by a factor of

$\frac{1}{r^{2}}$

(the reciprocal of equation 18) at the marker in comparison with the disease-association locus.

Therefore, if one calculated the power to detect disease-association indirectly with an experiment having N samples, then equivalent power to directly detect disease-association (at the actual disease-susceptibility locus) would necessitate an experiment using approximately r²N samples. This elementary relationship between power, sample size and linkage disequilibrium can be used to derive an r² threshold value useful in determining whether or not genotyping markers in linkage disequilibrium with a SNP marker directly associated with disease status has enough power to indirectly detect disease-association.

To commence a derivation of the power to detect disease-associated markers through an indirect process, define the effective chromosomal sample size as

$\begin{matrix} {{n = \frac{4N_{cs}N_{ct}}{N_{cs} + N_{ct}}};} & (27) \end{matrix}$

where N_(cs) and N_(ct) are the numbers of diploid cases and controls, respectively. This is necessary to handle situations where the numbers of cases and controls are not equivalent. For equal case and control sample sizes, N_(cs)=N_(ct)=N, the value of the effective number of chromosomes is simply n=2N—as expected. Let power be calculated for a significance level α (such that traditional P-values below α will be deemed statistically significant). Define the standard Gaussian distribution function as Φ(•). Mathematically,

$\begin{matrix} {{\Phi (x)} = {\frac{1}{\sqrt{2\pi}}{\int_{- \infty}^{x}{^{- \frac{\theta^{2}}{2}}\ {\theta}}}}} & (28) \end{matrix}$

Alternatively, the following error function notation (Erf) may also be used,

$\begin{matrix} {{\Phi (x)} = {\frac{1}{2}\left\lbrack {1 + {{Erf}\left( \frac{x}{\sqrt{2}} \right)}} \right\rbrack}} & (29) \end{matrix}$

For example, Φ(1.644854)=0.95. The value of r² may be derived to yield a pre-specified minimum amount of power to detect disease association though indirect interrogation. Noting that the LD SNP marker could be the one that is carrying the disease-association allele, therefore that this approach constitutes a lower-bound model where all indirect power results are expected to be at least as large as those interrogated.

Denote by β the error rate for not detecting truly disease-associated markers. Therefore, 1−β is the classical definition of statistical power. Substituting the Pritchard-Pzreworski result into the sample size, the power to detect disease association at a significance level of α is given by the approximation

$\begin{matrix} {{{1 - \beta} \cong {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - \frac{\alpha}{2}}} \right\rbrack}};} & (30) \end{matrix}$

where Z_(u) is the inverse of the standard normal cumulative distribution evaluated at u (uε(0,1)). Z_(u)=Φ⁻¹(u), where Φ(Φ⁻¹(u))=Φ⁻¹(Φ(u))=u. For example, setting α=0.05, and therefore 1−α/2=0.975, one obtains Z_(0.975)=1.95996. Next, setting power equal to a threshold of a minimum power of T,

$\begin{matrix} {T = {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - \frac{\alpha}{2}}} \right\rbrack}} & (31) \end{matrix}$

and solving for r², the following threshold r² is obtained:

$\begin{matrix} {r_{T}^{2} = {\frac{\left\lbrack {{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}} \right\rbrack}{{n\left( {q_{1,{cs}} - q_{1,{ct}}} \right)}^{2}}\left\lbrack {{\Phi^{- 1}(T)} + Z_{1 - \frac{\alpha}{2}}} \right\rbrack}^{2}} & (32) \end{matrix}$

Or,

$\begin{matrix} {r_{T}^{2} = {\frac{\left( {Z_{T} + Z_{1 - \frac{\alpha}{2}}} \right)^{2}}{n}\left\lbrack \frac{q_{1,{cs}} - \left( q_{1,{cs}} \right)^{2} + q_{1,{ct}} - \left( q_{1,{ct}} \right)^{2}}{\left( {q_{1,{cs}} - q_{1,{ct}}} \right)^{2}} \right\rbrack}} & (33) \end{matrix}$

Suppose that r² is calculated between an interrogated SNP and a number of other SNPs with varying levels of LD with the interrogated SNP. The threshold value r_(T) ² is the minimum value of linkage disequilibrium between the interrogated SNP and the potential LD SNPs such that the LD SNP still retains a power greater or equal to T for detecting disease-association. For example, suppose that SNP rs200 is genotyped in a case-control disease-association study and it is found to be associated with a disease phenotype. Further suppose that the minor allele frequency in 1,000 case chromosomes was found to be 16% in contrast with a minor allele frequency of 10% in 1,000 control chromosomes. Given those measurements one could have predicted, prior to the experiment, that the power to detect disease association at a significance level of 0.05 was quite high—approximately 98% using a test of allelic association. Applying equation (32) one can calculate a minimum value of r² to indirectly assess disease association assuming that the minor allele at SNP rs200 is truly disease-predisposing for a threshold level of power. If one sets the threshold level of power to be 80%, then r_(T) ²=0.489 given the same significance level and chromosome numbers as above. Hence, any SNP with a pairwise r² value with rs200 greater than 0.489 is expected to have greater than 80% power to detect the disease association. Further, this is assuming the conservative model where the LD SNP is disease-associated only through linkage disequilibrium with the interrogated SNP rs200.

The contribution or association of particular SNPs and/or SNP haplotypes with disease phenotypes, such as autoimmune disease, enables the SNPs of the present invention to be used to develop superior diagnostic tests capable of identifying individuals who express a detectable trait, such as autoimmune disease, as the result of a specific genotype, or individuals whose genotype places them at an increased or decreased risk of developing a detectable trait at a subsequent time as compared to individuals who do not have that genotype. As described herein, diagnostics may be based on a single SNP or a group of SNPs. Combined detection of a plurality of SNPs (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between, or more, of the SNPs provided in Table 1 and/or Table 2) typically increases the probability of an accurate diagnosis. For example, the presence of a single SNP known to correlate with autoimmune disease might indicate a probability of 20% that an individual has or is at risk of developing autoimmune disease, whereas detection of five SNPs, each of which correlates with autoimmune disease, might indicate a probability of 80% that an individual has or is at risk of developing autoimmune disease. To further increase the accuracy of diagnosis or predisposition screening, analysis of the SNPs of the present invention can be combined with that of other polymorphisms or other risk factors of autoimmune disease, such as disease symptoms, pathological characteristics, family history, diet, environmental factors or lifestyle factors.

It will be understood by practitioners skilled in the treatment or diagnosis of autoimmune disease that the present invention generally does not intend to provide an absolute identification of individuals who are at risk (or less at risk) of developing autoimmune disease, and/or pathologies related to autoimmune disease, but rather to indicate a certain increased (or decreased) degree or likelihood of developing the disease based on statistically significant association results. However, this information is extremely valuable as it can be used to, for example, initiate preventive treatments or to allow an individual carrying one or more significant SNPs or SNP haplotypes to foresee warning signs such as minor clinical symptoms, or to have regularly scheduled physical exams to monitor for appearance of a condition in order to identify and begin treatment of the condition at an early stage. Particularly with diseases that are extremely debilitating or fatal if not treated on time, the knowledge of a potential predisposition, even if this predisposition is not absolute, would likely contribute in a very significant manner to treatment efficacy.

The diagnostic techniques of the present invention may employ a variety of methodologies to determine whether a test subject has a SNP or a SNP pattern associated with an increased or decreased risk of developing a detectable trait or whether the individual suffers from a detectable trait as a result of a particular polymorphism/mutation, including, for example, methods which enable the analysis of individual chromosomes for haplotyping, family studies, single sperm DNA analysis, or somatic hybrids. The trait analyzed using the diagnostics of the invention may be any detectable trait that is commonly observed in pathologies and disorders related to autoimmune disease.

Another aspect of the present invention relates to a method of determining whether an individual is at risk (or less at risk) of developing one or more traits or whether an individual expresses one or more traits as a consequence of possessing a particular trait-causing or trait-influencing allele. These methods generally involve obtaining a nucleic acid sample from an individual and assaying the nucleic acid sample to determine which nucleotide(s) is/are present at one or more SNP positions, wherein the assayed nucleotide(s) is/are indicative of an increased or decreased risk of developing the trait or indicative that the individual expresses the trait as a result of possessing a particular trait-causing or trait-influencing allele.

In another embodiment, the SNP detection reagents of the present invention are used to determine whether an individual has one or more SNP allele(s) affecting the level (e.g., the concentration of mRNA or protein in a sample, etc.) or pattern (e.g., the kinetics of expression, rate of decomposition, stability profile, Km, Vmax, etc.) of gene expression (collectively, the “gene response” of a cell or bodily fluid). Such a determination can be accomplished by screening for mRNA or protein expression (e.g., by using nucleic acid arrays, RT-PCR, TaqMan assays, or mass spectrometry), identifying genes having altered expression in an individual, genotyping SNPs disclosed in Table 1 and/or Table 2 that could affect the expression of the genes having altered expression (e.g., SNPs that are in and/or around the gene(s) having altered expression, SNPs in regulatory/control regions, SNPs in and/or around other genes that are involved in pathways that could affect the expression of the gene(s) having altered expression, or all SNPs could be genotyped), and correlating SNP genotypes with altered gene expression. In this manner, specific SNP alleles at particular SNP sites can be identified that affect gene expression.

Therapeutics, Pharmacogenomics, and Drug Development

Therapeutic Methods and Compositions

In certain aspects of the invention, there are provided methods of assaying (i.e., testing) one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a therapeutic or preventive agent to the individual based on the allele(s) present at the SNP(s) having indicated that the individual can benefit from the therapeutic or preventive agent.

In further aspects of the invention, there are provided methods of assaying one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a diagnostic agent (e.g., an imaging agent), or otherwise carrying out further diagnostic procedures on the individual, based on the allele(s) present at the SNP(s) having indicated that the diagnostic agents or diagnostics procedures are justified in the individual.

In yet other aspects of the invention, there is provided a pharmaceutical pack comprising a therapeutic agent (e.g., a small molecule drug, antibody, peptide, antisense or RNAi nucleic acid molecule, etc.) and a set of instructions for administration of the therapeutic agent to an individual who has been tested for one or more SNPs provided by the present invention.

Pharmacogenomics

The present invention provides methods for assessing the pharmacogenomics of a subject harboring particular SNP alleles or haplotypes to a particular therapeutic agent or pharmaceutical compound, or to a class of such compounds. Pharmacogenomics deals with the roles which clinically significant hereditary variations (e.g., SNPs) play in the response to drugs due to altered drug disposition and/or abnormal action in affected persons. See, e.g., Roses, Nature 405, 857-865 (2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001); Eichelbaum, Clin Exp Pharmacol Physiol 23(10-11):983-985 (1996); and Linder, Clin Chem 43(2):254-266 (1997). The clinical outcomes of these variations can result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the SNP genotype of an individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. For example, SNPs in drug-metabolizing enzymes can affect the activity of these enzymes, which in turn can affect both the intensity and duration of drug action, as well as drug metabolism and clearance.

The discovery of SNPs in drug-metabolizing enzymes, drug-transporters, proteins for pharmaceutical agents, and other drug targets has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. SNPs can be expressed in the phenotype of the extensive metabolizer and in the phenotype of the poor metabolizer. Accordingly, SNPs may lead to allelic variants of a protein in which one or more of the protein functions in one population are different from those in another population. SNPs and the encoded variant peptides thus provide targets to ascertain a genetic predisposition that can affect treatment modality. For example, in a ligand-based treatment, SNPs may give rise to amino terminal extracellular domains and/or other ligand-binding regions of a receptor that are more or less active in ligand binding, thereby affecting subsequent protein activation. Accordingly, ligand dosage would necessarily be modified to maximize the therapeutic effect within a given population containing particular SNP alleles or haplotypes.

As an alternative to genotyping, specific variant proteins containing variant amino acid sequences encoded by alternative SNP alleles could be identified. Thus, pharmacogenomic characterization of an individual permits the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic uses based on the individual's SNP genotype, thereby enhancing and optimizing the effectiveness of the therapy. Furthermore, the production of recombinant cells and transgenic animals containing particular SNPs/haplotypes allow effective clinical design and testing of treatment compounds and dosage regimens. For example, transgenic animals can be produced that differ only in specific SNP alleles in a gene that is orthologous to a human disease susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provide several significant advantages for patient care, particularly in predicting an individual's predisposition to autoimmune disease (e.g., RA) and in predicting an individual's responsiveness to a drug (particularly for treating or preventing autoimmune disease). Pharmacogenomic characterization of an individual, based on an individual's SNP genotype, can identify those individuals unlikely to respond to treatment with a particular medication and thereby allows physicians to avoid prescribing the ineffective medication to those individuals. On the other hand, SNP genotyping of an individual may enable physicians to select the appropriate medication and dosage regimen that will be most effective based on an individual's SNP genotype. This information increases a physician's confidence in prescribing medications and motivates patients to comply with their drug regimens. Furthermore, pharmacogenomics may identify patients predisposed to toxicity and adverse reactions to particular drugs or drug dosages. Adverse drug reactions lead to more than 100,000 avoidable deaths per year in the United States alone and therefore represent a significant cause of hospitalization and death, as well as a significant economic burden on the healthcare system (Pfost et al., Trends in Biotechnology, August 2000). Thus, pharmacogenomics based on the SNPs disclosed herein has the potential to both save lives and reduce healthcare costs substantially.

Pharmacogenomics in general is discussed further in Rose et al., “Pharmacogenetic analysis of clinically relevant genetic polymorphisms,” Methods Mol Med 85:225-37 (2003). Pharmacogenomics as it relates to Alzheimer's disease and other neurodegenerative disorders is discussed in Cacabelos, “Pharmacogenomics for the treatment of dementia,” Ann Med 34(5):357-79 (2002); Maimone et al., “Pharmacogenomics of neurodegenerative diseases,” Eur J Pharmacol 413(1):11-29 (February 2001); and Poirier, “Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease,” Mol Diagn 4(4):335-41 (December 1999). Pharmacogenomics as it relates to cardiovascular disorders is discussed in Siest et al., “Pharmacogenomics of drugs affecting the cardiovascular system,” Clin Chem Lab Med 41(4):590-9 (April 2003); Mukherjee et al., “Pharmacogenomics in cardiovascular diseases,” Prog Cardiovasc Dis 44(6):479-98 (May-June 2002); and Mooser et al., “Cardiovascular pharmacogenetics in the SNP era,” J Thromb Haemost 1(7):1398-402 (July 2003). Pharmacogenomics as it relates to cancer is discussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, and the individual patient,” Cancer Invest 21(4):630-40 (2003); and Watters et al., “Cancer pharmacogenomics: current and future applications,” Biochim Biophys Acta 1603(2):99-111 (March 2003).

Clinical Trials

In certain aspects of the invention, there are provided methods of using the SNPs disclosed herein to identify or stratify patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent.

For instance, an aspect of the present invention includes selecting individuals for clinical trials based on their SNP genotype. For example, individuals with SNP genotypes that indicate that they are likely to positively respond to a drug can be included in the trials, whereas those individuals whose SNP genotypes indicate that they are less likely to or would not respond to the drug, or who are at risk for suffering toxic effects or other adverse reactions, can be excluded from the clinical trials. This not only can improve the safety of clinical trials, but also can enhance the chances that the trial will demonstrate statistically significant efficacy.

In certain exemplary embodiments, SNPs of the invention can be used to select individuals who are unlikely to respond positively to a particular therapeutic agent (or class of therapeutic agents) based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them. Thus, in certain embodiments, the SNPs of the invention can be used to identify patient populations who do not adequately respond to current treatments and are therefore in need of new therapies. This not only benefits the patients themselves, but also benefits organizations such as pharmaceutical companies by enabling the identification of populations that represent markets for new drugs, and enables the efficacy of these new drugs to be tested during clinical trials directly in individuals within these markets.

The SNP-containing nucleic acid molecules of the present invention are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of a variant gene, or encoded product, particularly in a treatment regimen or in clinical trials. Thus, the gene expression pattern can serve as an indicator for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance, as well as an indicator for toxicities. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant.

Furthermore, the SNPs of the present invention may have utility in determining why certain previously developed drugs performed poorly in clinical trials and may help identify a subset of the population that would benefit from a drug that had previously performed poorly in clinical trials, thereby “rescuing” previously developed drugs, and enabling the drug to be made available to a particular autoimmune disease patient population that can benefit from it.

Identification, Screening, and Use of Therapeutic Agents

The SNPs of the present invention also can be used to identify novel therapeutic targets for autoimmune disease. For example, genes containing the disease-associated variants (“variant genes”) or their products, as well as genes or their products that are directly or indirectly regulated by or interacting with these variant genes or their products, can be targeted for the development of therapeutics that, for example, treat the disease or prevent or delay disease onset. The therapeutics may be composed of, for example, small molecules, proteins, protein fragments or peptides, antibodies, nucleic acids, or their derivatives or mimetics which modulate the functions or levels of the target genes or gene products.

The invention further provides methods for identifying a compound or agent that can be used to treat autoimmune disease. The SNPs disclosed herein are useful as targets for the identification and/or development of therapeutic agents. A method for identifying a therapeutic agent or compound typically includes assaying the ability of the agent or compound to modulate the activity and/or expression of a SNP-containing nucleic acid or the encoded product and thus identifying an agent or a compound that can be used to treat a disorder characterized by undesired activity or expression of the SNP-containing nucleic acid or the encoded product. The assays can be performed in cell-based and cell-free systems. Cell-based assays can include cells naturally expressing the nucleic acid molecules of interest or recombinant cells genetically engineered to express certain nucleic acid molecules.

Variant gene expression in a autoimmune disease patient can include, for example, either expression of a SNP-containing nucleic acid sequence (for instance, a gene that contains a SNP can be transcribed into an mRNA transcript molecule containing the SNP, which can in turn be translated into a variant protein) or altered expression of a normal/wild-type nucleic acid sequence due to one or more SNPs (for instance, a regulatory/control region can contain a SNP that affects the level or pattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleic acid levels (e.g., mRNA levels), expressed protein levels, or of collateral compounds involved in a signal pathway. Further, the expression of genes that are up- or down-regulated in response to the signal pathway can also be assayed. In this embodiment, the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.

Modulators of variant gene expression can be identified in a method wherein, for example, a cell is contacted with a candidate compound/agent and the expression of mRNA determined. The level of expression of mRNA in the presence of the candidate compound is compared to the level of expression of mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of variant gene expression based on this comparison and be used to treat a disorder such as autoimmune disease that is characterized by variant gene expression (e.g., either expression of a SNP-containing nucleic acid or altered expression of a normal/wild-type nucleic acid molecule due to one or more SNPs that affect expression of the nucleic acid molecule) due to one or more SNPs of the present invention. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP or associated nucleic acid domain (e.g., catalytic domain, ligand/substrate-binding domain, regulatory/control region, etc.) or gene, or the encoded mRNA transcript, as a target, using a compound identified through drug screening as a gene modulator to modulate variant nucleic acid expression. Modulation can include either up-regulation (i.e., activation or agonization) or down-regulation (i.e., suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type or variant, may be altered in individuals with a particular SNP allele in a regulatory/control element, such as a promoter or transcription factor binding domain, that regulates expression. In this situation, methods of treatment and compounds can be identified, as discussed herein, that regulate or overcome the variant regulatory/control element, thereby generating normal, or healthy, expression levels of either the wild type or variant protein.

Pharmaceutical Compositions and Administration Thereof

Any of the autoimmune disease-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating or preventing autoimmune disease or related pathologies, and the present disclosure enables therapeutic compounds (e.g., small molecules, antibodies, therapeutic proteins, RNAi and antisense molecules, etc.) to be developed that target (or are comprised of) any of these therapeutic targets.

In general, a therapeutic compound will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the therapeutic compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.

Therapeutically effective amounts of therapeutic compounds may range from, for example, approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as an example, for administration to a 70-kg person, the dosage range would most preferably be about 7 mg to 1.4 g per day.

In general, therapeutic compounds will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeutic compound in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the therapeutic compound. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences 18^(th) ed., E. W. Martin, ed., Mack Publishing Company (1990).

The amount of the therapeutic compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of the therapeutic compound based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80% wt.

Therapeutic compounds can be administered alone or in combination with other therapeutic compounds or in combination with one or more other active ingredient(s). For example, an inhibitor or stimulator of a autoimmune disease-associated protein can be administered in combination with another agent that inhibits or stimulates the activity of the same or a different autoimmune disease-associated protein to thereby counteract the effects of autoimmune disease.

For further information regarding pharmacology, see Current Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.

Nucleic Acid-Based Therapeutic Agents

The SNP-containing nucleic acid molecules disclosed herein, and their complementary nucleic acid molecules, may be used as antisense constructs to control gene expression in cells, tissues, and organisms. Antisense technology is well established in the art and extensively reviewed in Antisense Drug Technology: Principles, Strategies, and Applications, Crooke, ed., Marcel Dekker, Inc., N.Y. (2001). An antisense nucleic acid molecule is generally designed to be complementary to a region of mRNA expressed by a gene so that the antisense molecule hybridizes to the mRNA and thereby blocks translation of mRNA into protein. Various classes of antisense oligonucleotides are used in the art, two of which are cleavers and blockers. Cleavers, by binding to target RNAs, activate intracellular nucleases (e.g., RNaseH or RNase L) that cleave the target RNA. Blockers, which also bind to target RNAs, inhibit protein translation through steric hindrance of ribosomes. Exemplary blockers include peptide nucleic acids, morpholinos, locked nucleic acids, and methylphosphonates. See, e.g., Thompson, Drug Discovery Today 7(17): 912-917 (2002). Antisense oligonucleotides are directly useful as therapeutic agents, and are also useful for determining and validating gene function (e.g., in gene knock-out or knock-down experiments).

Antisense technology is further reviewed in: Layery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July 2003); Stephens et al., “Antisense oligonucleotide therapy in cancer,” Curr Opin Mol Ther 5(2):118-22 (April 2003); Kurreck, “Antisense technologies. Improvement through novel chemical modifications,” Eur J Biochem 270(8):1628-44 (April 2003); Dias et al., “Antisense oligonucleotides: basic concepts and mechanisms,” Mol Cancer Ther 1(5):347-55 (March 2002); Chen, “Clinical development of antisense oligonucleotides as anti-cancer therapeutics,” Methods Mol Med 75:621-36 (2003); Wang et al., “Antisense anticancer oligonucleotide therapeutics,” Curr Cancer Drug Targets 1(3):177-96 (November 2001); and Bennett, “Efficiency of antisense oligonucleotide drug discovery,” Antisense Nucleic Acid Drug Dev 12(3):215-24 (June 2002).

The SNPs of the present invention are particularly useful for designing antisense reagents that are specific for particular nucleic acid variants. Based on the SNP information disclosed herein, antisense oligonucleotides can be produced that specifically target mRNA molecules that contain one or more particular SNP nucleotides. In this manner, expression of mRNA molecules that contain one or more undesired polymorphisms (e.g., SNP nucleotides that lead to a defective protein such as an amino acid substitution in a catalytic domain) can be inhibited or completely blocked. Thus, antisense oligonucleotides can be used to specifically bind a particular polymorphic form (e.g., a SNP allele that encodes a defective protein), thereby inhibiting translation of this form, but which do not bind an alternative polymorphic form (e.g., an alternative SNP nucleotide that encodes a protein having normal function).

Antisense molecules can be used to inactivate mRNA in order to inhibit gene expression and production of defective proteins. Accordingly, these molecules can be used to treat a disorder, such as autoimmune disease, characterized by abnormal or undesired gene expression or expression of certain defective proteins. This technique can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible mRNA regions include, for example, protein-coding regions and particularly protein-coding regions corresponding to catalytic activities, substrate/ligand binding, or other functional activities of a protein.

The SNPs of the present invention are also useful for designing RNA interference reagents that specifically target nucleic acid molecules having particular SNP variants. RNA interference (RNAi), also referred to as gene silencing, is based on using double-stranded RNA (dsRNA) molecules to turn genes off. When introduced into a cell, dsRNAs are processed by the cell into short fragments (generally about 21, 22, or 23 nucleotides in length) known as small interfering RNAs (siRNAs) which the cell uses in a sequence-specific manner to recognize and destroy complementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917 (2002). Accordingly, an aspect of the present invention specifically contemplates isolated nucleic acid molecules that are about 18-26 nucleotides in length, preferably 19-25 nucleotides in length, and more preferably 20, 21, 22, or 23 nucleotides in length, and the use of these nucleic acid molecules for RNAi. Because RNAi molecules, including siRNAs, act in a sequence-specific manner, the SNPs of the present invention can be used to design RNAi reagents that recognize and destroy nucleic acid molecules having specific SNP alleles/nucleotides (such as deleterious alleles that lead to the production of defective proteins), while not affecting nucleic acid molecules having alternative SNP alleles (such as alleles that encode proteins having normal function). As with antisense reagents, RNAi reagents may be directly useful as therapeutic agents (e.g., for turning off defective, disease-causing genes), and are also useful for characterizing and validating gene function (e.g., in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds et al., “Rational siRNA design for RNA interference,” Nat Biotechnol 22(3):326-30 (March 2004); Epub Feb. 1, 2004; Chi et al., “Genomewide view of gene silencing by small interfering RNAs,” PNAS 100(11):6343-6346 (2003); Vickers et al., “Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents,” J Biol Chem 278:7108-7118 (2003); Agami, “RNAi and related mechanisms and their potential use for therapy,” Curr Opin Chem Biol 6(6):829-34 (December 2002); Lavery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July 2003); Shi, “Mammalian RNAi for the masses,” Trends Genet. 19(1):9-12 (January 2003); Shuey et al., “RNAi: gene-silencing in therapeutic intervention,” Drug Discovery Today 7(20):1040-1046 (October 2002); McManus et al., Nat Rev Genet. 3(10):737-47 (October 2002); Xia et al., Nat Biotechnol 20(10):1006-10 (October 2002); Plasterk et al., Curr Opin Genet Dev 10(5):562-7 (October 2000); Bosher et al., Nat Cell Biol 2(2):E31-6 (February 2000); and Hunter, Curr Biol 17; 9(12):R440-2 (June 1999).

Other Therapeutic Aspects

SNPs have many important uses in drug discovery, screening, and development, and thus the SNPs of the present invention are useful for improving many different aspects of the drug development process.

For example, a high probability exists that, for any gene/protein selected as a potential drug target, variants of that gene/protein will exist in a patient population. Thus, determining the impact of gene/protein variants on the selection and delivery of a therapeutic agent should be an integral aspect of the drug discovery and development process. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (March 2002).

Knowledge of variants (e.g., SNPs and any corresponding amino acid polymorphisms) of a particular therapeutic target (e.g., a gene, mRNA transcript, or protein) enables parallel screening of the variants in order to identify therapeutic candidates (e.g., small molecule compounds, antibodies, antisense or RNAi nucleic acid compounds, etc.) that demonstrate efficacy across variants. Rothberg, Nat Biotechnol 19(3):209-11 (March 2001). Such therapeutic candidates would be expected to show equal efficacy across a larger segment of the patient population, thereby leading to a larger potential market for the therapeutic candidate.

Furthermore, identifying variants of a potential therapeutic target enables the most common form of the target to be used for selection of therapeutic candidates, thereby helping to ensure that the experimental activity that is observed for the selected candidates reflects the real activity expected in the largest proportion of a patient population. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (March 2002).

Additionally, screening therapeutic candidates against all known variants of a target can enable the early identification of potential toxicities and adverse reactions relating to particular variants. For example, variability in drug absorption, distribution, metabolism and excretion (ADME) caused by, for example, SNPs in therapeutic targets or drug metabolizing genes, can be identified, and this information can be utilized during the drug development process to minimize variability in drug disposition and develop therapeutic agents that are safer across a wider range of a patient population. The SNPs of the present invention, including the variant proteins and encoding polymorphic nucleic acid molecules provided in Tables 1 and 2, are useful in conjunction with a variety of toxicology methods established in the art, such as those set forth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (or nucleic acid molecules, either RNA or DNA) may cross-react with the variant proteins (or polymorphic nucleic acid molecules) disclosed in Table 1, thereby significantly affecting the pharmacokinetic properties of the drug. Consequently, the protein variants and the SNP-containing nucleic acid molecules disclosed in Tables 1 and 2 are useful in developing, screening, and evaluating therapeutic agents that target corresponding art-known protein forms (or nucleic acid molecules). Additionally, as discussed above, knowledge of all polymorphic forms of a particular drug target enables the design of therapeutic agents that are effective against most or all such polymorphic forms of the drug target.

A subject suffering from a pathological condition ascribed to a SNP, such as autoimmune disease, may be treated so as to correct the genetic defect. See Kren et al., Proc Nall Acad Sci USA 96:10349-10354 (1999). Such a subject can be identified by any method that can detect the polymorphism in a biological sample drawn from the subject. Such a genetic defect may be permanently corrected by administering to such a subject a nucleic acid fragment incorporating a repair sequence that supplies the normal/wild-type nucleotide at the position of the SNP. This site-specific repair sequence can encompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The site-specific repair sequence is administered in an appropriate vehicle, such as a complex with polyethylenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus, or other pharmaceutical composition that promotes intracellular uptake of the administered nucleic acid. A genetic defect leading to an inborn pathology may then be overcome, as the chimeric oligonucleotides induce incorporation of the normal sequence into the subject's genome. Upon incorporation, the normal gene product is expressed, and the replacement is propagated, thereby engendering a permanent repair and therapeutic enhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribed to be the cause of, or a contributing factor to, a pathological condition, a method of treating such a condition can include administering to a subject experiencing the pathology the wild-type/normal cognate of the variant protein. Once administered in an effective dosing regimen, the wild-type cognate provides complementation or remediation of the pathological condition.

Human Identification Applications

In addition to their predictive, diagnostic, prognostic, therapeutic, and preventive uses in autoimmune disease and related pathologies, the SNPs provided by the present invention are also useful as human identification markers for such applications as forensics, paternity testing, and biometrics. See, e.g., Gill, “An assessment of the utility of single nucleotide polymorphisms (SNPs) for forensic purposes,” Int J Legal Med 114(4-5):204-10 (2001). Genetic variations in the nucleic acid sequences between individuals can be used as genetic markers to identify individuals and to associate a biological sample with an individual. Determination of which nucleotides occupy a set of SNP positions in an individual identifies a set of SNP markers that distinguishes the individual. The more SNP positions that are analyzed, the lower the probability that the set of SNPs in one individual is the same as that in an unrelated individual. Preferably, if multiple sites are analyzed, the sites are unlinked (i.e., inherited independently). Thus, preferred sets of SNPs can be selected from among the SNPs disclosed herein, which may include SNPs on different chromosomes, SNPs on different chromosome arms, and/or SNPs that are dispersed over substantial distances along the same chromosome arm.

Furthermore, among the SNPs disclosed herein, preferred SNPs for use in certain forensic/human identification applications include SNPs located at degenerate codon positions (i.e., the third position in certain codons which can be one of two or more alternative nucleotides and still encode the same amino acid), since these SNPs do not affect the encoded protein. SNPs that do not affect the encoded protein are expected to be under less selective pressure and are therefore expected to be more polymorphic in a population, which is typically an advantage for forensic/human identification applications. However, for certain forensics/human identification applications, such as predicting phenotypic characteristics (e.g., inferring ancestry or inferring one or more physical characteristics of an individual) from a DNA sample, it may be desirable to utilize SNPs that affect the encoded protein.

For many of the SNPs disclosed in Tables 1 and 2 (which are identified as “Applera” SNP source), Tables 1 and 2 provide SNP allele frequencies obtained by re-sequencing the DNA of chromosomes from 39 individuals (Tables 1 and 2 also provide allele frequency information for “Celera” source SNPs and, where available, public SNPs from dbEST, HGBASE, and/or HGMD). The allele frequencies provided in Tables 1 and 2 enable these SNPs to be readily used for human identification applications. Although any SNP disclosed in Table 1 and/or Table 2 could be used for human identification, the closer that the frequency of the minor allele at a particular SNP site is to 50%, the greater the ability of that SNP to discriminate between different individuals in a population since it becomes increasingly likely that two randomly selected individuals would have different alleles at that SNP site. Using the SNP allele frequencies provided in Tables 1 and 2, one of ordinary skill in the art could readily select a subset of SNPs for which the frequency of the minor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables 1 and 2 provide allele frequencies based on the re-sequencing of the chromosomes from 39 individuals, a subset of SNPs could readily be selected for human identification in which the total allele count of the minor allele at a particular SNP site is, for example, at least 1, 2, 4, 8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other number in-between.

Furthermore, Tables 1 and 2 also provide population group (interchangeably referred to herein as ethnic or racial groups) information coupled with the extensive allele frequency information. For example, the group of 39 individuals whose DNA was re-sequenced was made-up of 20 Caucasians and 19 African-Americans. This population group information enables further refinement of SNP selection for human identification. For example, preferred SNPs for human identification can be selected from Tables 1 and 2 that have similar allele frequencies in both the Caucasian and African-American populations; thus, for example, SNPs can be selected that have equally high discriminatory power in both populations. Alternatively, SNPs can be selected for which there is a statistically significant difference in allele frequencies between the Caucasian and African-American populations (as an extreme example, a particular allele may be observed only in either the Caucasian or the African-American population group but not observed in the other population group); such SNPs are useful, for example, for predicting the race/ethnicity of an unknown perpetrator from a biological sample such as a hair or blood stain recovered at a crime scene. For a discussion of using SNPs to predict ancestry from a DNA sample, including statistical methods, see Frudakis et al., “A Classifier for the SNP-Based Inference of Ancestry,” Journal of Forensic Sciences 48(4):771-782 (2003).

SNPs have numerous advantages over other types of polymorphic markers, such as short tandem repeats (STRs). For example, SNPs can be easily scored and are amenable to automation, making SNPs the markers of choice for large-scale forensic databases. SNPs are found in much greater abundance throughout the genome than repeat polymorphisms. Population frequencies of two polymorphic forms can usually be determined with greater accuracy than those of multiple polymorphic forms at multi-allelic loci. SNPs are mutationally more stable than repeat polymorphisms. SNPs are not susceptible to artifacts such as stutter bands that can hinder analysis. Stutter bands are frequently encountered when analyzing repeat polymorphisms, and are particularly troublesome when analyzing samples such as crime scene samples that may contain mixtures of DNA from multiple sources. Another significant advantage of SNP markers over STR markers is the much shorter length of nucleic acid needed to score a SNP. For example, STR markers are generally several hundred base pairs in length. A SNP, on the other hand, comprises a single nucleotide, and generally a short conserved region on either side of the SNP position for primer and/or probe binding. This makes SNPs more amenable to typing in highly degraded or aged biological samples that are frequently encountered in forensic casework in which DNA may be fragmented into short pieces.

SNPs also are not subject to microvariant and “off-ladder” alleles frequently encountered when analyzing STR loci. Microvariants are deletions or insertions within a repeat unit that change the size of the amplified DNA product so that the amplified product does not migrate at the same rate as reference alleles with normal sized repeat units. When separated by size, such as by electrophoresis on a polyacrylamide gel, microvariants do not align with a reference allelic ladder of standard sized repeat units, but rather migrate between the reference alleles. The reference allelic ladder is used for precise sizing of alleles for allele classification; therefore alleles that do not align with the reference allelic ladder lead to substantial analysis problems. Furthermore, when analyzing multi-allelic repeat polymorphisms, occasionally an allele is found that consists of more or less repeat units than has been previously seen in the population, or more or less repeat alleles than are included in a reference allelic ladder. These alleles will migrate outside the size range of known alleles in a reference allelic ladder, and therefore are referred to as “off-ladder” alleles. In extreme cases, the allele may contain so few or so many repeats that it migrates well out of the range of the reference allelic ladder. In this situation, the allele may not even be observed, or, with multiplex analysis, it may migrate within or close to the size range for another locus, further confounding analysis.

SNP analysis avoids the problems of microvariants and off-ladder alleles encountered in STR analysis. Importantly, microvariants and off-ladder alleles may provide significant problems, and may be completely missed, when using analysis methods such as oligonucleotide hybridization arrays, which utilize oligonucleotide probes specific for certain known alleles. Furthermore, off-ladder alleles and microvariants encountered with STR analysis, even when correctly typed, may lead to improper statistical analysis, since their frequencies in the population are generally unknown or poorly characterized, and therefore the statistical significance of a matching genotype may be questionable. All these advantages of SNP analysis are considerable in light of the consequences of most DNA identification cases, which may lead to life imprisonment for an individual, or re-association of remains to the family of a deceased individual.

DNA can be isolated from biological samples such as blood, bone, hair, saliva, or semen, and compared with the DNA from a reference source at particular SNP positions. Multiple SNP markers can be assayed simultaneously in order to increase the power of discrimination and the statistical significance of a matching genotype. For example, oligonucleotide arrays can be used to genotype a large number of SNPs simultaneously. The SNPs provided by the present invention can be assayed in combination with other polymorphic genetic markers, such as other SNPs known in the art or STRs, in order to identify an individual or to associate an individual with a particular biological sample.

Furthermore, the SNPs provided by the present invention can be genotyped for inclusion in a database of DNA genotypes, for example, a criminal DNA databank such as the FBI's Combined DNA Index System (CODIS) database. A genotype obtained from a biological sample of unknown source can then be queried against the database to find a matching genotype, with the SNPs of the present invention providing nucleotide positions at which to compare the known and unknown DNA sequences for identity. Accordingly, the present invention provides a database comprising novel SNPs or SNP alleles of the present invention (e.g., the database can comprise information indicating which alleles are possessed by individual members of a population at one or more novel SNP sites of the present invention), such as for use in forensics, biometrics, or other human identification applications. Such a database typically comprises a computer-based system in which the SNPs or SNP alleles of the present invention are recorded on a computer readable medium.

The SNPs of the present invention can also be assayed for use in paternity testing. The object of paternity testing is usually to determine whether a male is the father of a child. In most cases, the mother of the child is known and thus, the mother's contribution to the child's genotype can be traced. Paternity testing investigates whether the part of the child's genotype not attributable to the mother is consistent with that of the putative father. Paternity testing can be performed by analyzing sets of polymorphisms in the putative father and the child, with the SNPs of the present invention providing nucleotide positions at which to compare the putative father's and child's DNA sequences for identity. If the set of polymorphisms in the child attributable to the father does not match the set of polymorphisms of the putative father, it can be concluded, barring experimental error, that the putative father is not the father of the child. If the set of polymorphisms in the child attributable to the father match the set of polymorphisms of the putative father, a statistical calculation can be performed to determine the probability of coincidental match, and a conclusion drawn as to the likelihood that the putative father is the true biological father of the child.

In addition to paternity testing, SNPs are also useful for other types of kinship testing, such as for verifying familial relationships for immigration purposes, or for cases in which an individual alleges to be related to a deceased individual in order to claim an inheritance from the deceased individual, etc. For further information regarding the utility of SNPs for paternity testing and other types of kinship testing, including methods for statistical analysis, see Krawczak, “Informativity assessment for biallelic single nucleotide polymorphisms,” Electrophoresis 20(8):1676-81 (June 1999).

The use of the SNPs of the present invention for human identification further extends to various authentication systems, commonly referred to as biometric systems, which typically convert physical characteristics of humans (or other organisms) into digital data. Biometric systems include various technological devices that measure such unique anatomical or physiological characteristics as finger, thumb, or palm prints; hand geometry; vein patterning on the back of the hand; blood vessel patterning of the retina and color and texture of the iris; facial characteristics; voice patterns; signature and typing dynamics; and DNA. Such physiological measurements can be used to verify identity and, for example, restrict or allow access based on the identification. Examples of applications for biometrics include physical area security, computer and network security, aircraft passenger check-in and boarding, financial transactions, medical records access, government benefit distribution, voting, law enforcement, passports, visas and immigration, prisons, various military applications, and for restricting access to expensive or dangerous items, such as automobiles or guns. See, for example, O'Connor, Stanford Technology Law Review, and U.S. Pat. No. 6,119,096.

Groups of SNPs, particularly the SNPs provided by the present invention, can be typed to uniquely identify an individual for biometric applications such as those described above. Such SNP typing can readily be accomplished using, for example, DNA chips/arrays. Preferably, a minimally invasive means for obtaining a DNA sample is utilized. For example, PCR amplification enables sufficient quantities of DNA for analysis to be obtained from buccal swabs or fingerprints, which contain DNA-containing skin cells and oils that are naturally transferred during contact.

Further information regarding techniques for using SNPs in forensic/human identification applications can be found, for example, in Current Protocols in Human Genetics 14.1-14.7, John Wiley & Sons, N.Y. (2002).

Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules, many of which encode proteins having variant amino acid sequences as compared to the art-known (i.e., wild-type) proteins. Amino acid sequences encoded by the polymorphic nucleic acid molecules of the present invention are referred to as SEQ ID NOS:17-32 in Table 1 and provided in the Sequence Listing. These variants will generally be referred to herein as variant proteins/peptides/polypeptides, or polymorphic proteins/peptides/polypeptides of the present invention. The terms “protein,” “peptide,” and “polypeptide” are used herein interchangeably.

A variant protein of the present invention may be encoded by, for example, a nonsynonymous nucleotide substitution at any one of the cSNP positions disclosed herein. In addition, variant proteins may also include proteins whose expression, structure, and/or function is altered by a SNP disclosed herein, such as a SNP that creates or destroys a stop codon, a SNP that affects splicing, and a SNP in control/regulatory elements, e.g. promoters, enhancers, or transcription factor binding domains.

As used herein, a protein or peptide is said to be “isolated” or “purified” when it is substantially free of cellular material or chemical precursors or other chemicals. The variant proteins of the present invention can be purified to homogeneity or other lower degrees of purity. The level of purification will be based on the intended use. The key feature is that the preparation allows for the desired function of the variant protein, even if in the presence of considerable amounts of other components.

As used herein, “substantially free of cellular material” includes preparations of the variant protein having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the variant protein is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.

The language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant host cells), or synthesized using known protein synthesis methods. For example, a nucleic acid molecule containing SNP(s) encoding the variant protein can be cloned into an expression vector, the expression vector introduced into a host cell, and the variant protein expressed in the host cell. The variant protein can then be isolated from the cells by any appropriate purification scheme using standard protein purification techniques. Examples of these techniques are described in detail below. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The present invention provides isolated variant proteins that comprise, consist of or consist essentially of amino acid sequences that contain one or more variant amino acids encoded by one or more codons that contain a SNP of the present invention.

Accordingly, the present invention provides variant proteins that consist of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists of an amino acid sequence when the amino acid sequence is the entire amino acid sequence of the protein.

The present invention further provides variant proteins that consist essentially of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues in the final protein.

The present invention further provides variant proteins that comprise amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein may contain only the variant amino acid sequence or have additional amino acid residues, such as a contiguous encoded sequence that is naturally associated with it or heterologous amino acid residues. Such a protein can have a few additional amino acid residues or can comprise many more additional amino acids. A brief description of how various types of these proteins can be made and isolated is provided below.

The variant proteins of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a variant protein operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the variant protein. “Operatively linked” indicates that the coding sequences for the variant protein and the heterologous protein are ligated in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the variant protein. In another embodiment, the fusion protein is encoded by a fusion polynucleotide that is synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence. See Ausubel et al., Current Protocols in Molecular Biology (1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A variant protein-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the variant protein.

In many uses, the fusion protein does not affect the activity of the variant protein. The fusion protein can include, but is not limited to, enzymatic fusion proteins, for example, beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate their purification following recombinant expression. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Fusion proteins are further described in, for example, Terpe, “Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems,” Appl Microbiol Biotechnol 60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al., “Designing proteins that work using recombinant technologies,” Curr Pharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al., “Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins,” Protein Expr Purif 11(1):1-16 (October 1997).

In certain embodiments, novel compositions of the present invention also relate to further obvious variants of the variant polypeptides of the present invention, such as naturally-occurring mature forms (e.g., allelic variants), non-naturally occurring recombinantly-derived variants, and orthologs and paralogs of such proteins that share sequence homology. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry.

Further variants of the variant polypeptides disclosed in Table 1 can comprise an amino acid sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel amino acid residue (allele) disclosed in Table 1 (which is encoded by a novel SNP allele). Thus, an aspect of the present invention that is specifically contemplated are polypeptides that have a certain degree of sequence variation compared with the polypeptide sequences shown in Table 1, but that contain a novel amino acid residue (allele) encoded by a novel SNP allele disclosed herein. In other words, as long as a polypeptide contains a novel amino acid residue disclosed herein, other portions of the polypeptide that flank the novel amino acid residue can vary to some degree from the polypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, of proteins that comprise one of the amino acid sequences disclosed herein can readily be identified as having complete sequence identity to one of the variant proteins of the present invention as well as being encoded by the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of a variant peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from non-human mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs can be encoded by a nucleic acid sequence that hybridizes to a variant peptide-encoding nucleic acid molecule under moderate to stringent conditions depending on the degree of relatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containing deletions, additions and substitutions in the amino acid sequence caused by the SNPs of the present invention. One class of substitutions is conserved amino acid substitutions in which a given amino acid in a polypeptide is substituted for another amino acid of like characteristics. Typical conservative substitutions are replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found, for example, in Bowie et al., Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one or more activities, e.g. ability to bind another molecule, ability to catalyze a substrate, ability to mediate signaling, etc.

Fully functional variants typically contain only conservative variations or variations in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree. Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, truncations or extensions, or a substitution, insertion, inversion, or deletion of a critical residue or in a critical region.

Amino acids that are essential for function of a protein can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis, particularly using the amino acid sequence and polymorphism information provided in Table 1. Cunningham et al., Science 244:1081-1085 (1989). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as enzyme activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling. Smith et al., J Mol Biol 224:899-904 (1992); de Vos et al., Science 255:306-312 (1992).

Polypeptides can contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Accordingly, the variant proteins of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (e.g., polyethylene glycol), or in which additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.

Known protein modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

Such protein modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Particularly common modifications, for example glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, are described in most basic texts, such as Proteins—Structure and Molecular Properties 2nd Ed., T. E. Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold, Posttranslational Covalent Modification of Proteins 1-12, B. C. Johnson, ed., Academic Press, N.Y. (1983); Seifter et al., Meth Enzymol 182:626-646 (1990); and Rattan et al., Ann NY Acad Sci 663:48-62 (1992).

The present invention further provides fragments of the variant proteins in which the fragments contain one or more amino acid sequence variations (e.g., substitutions, or truncations or extensions due to creation or destruction of a stop codon) encoded by one or more SNPs disclosed herein. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that have been disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14, 16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or more contiguous amino acid residues from a variant protein, wherein at least one amino acid residue is affected by a SNP of the present invention, e.g., a variant amino acid residue encoded by a nonsynonymous nucleotide substitution at a cSNP position provided by the present invention. The variant amino acid encoded by a cSNP may occupy any residue position along the sequence of the fragment. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the variant protein or the ability to perform a function, e.g., act as an immunogen. Particularly important fragments are biologically active fragments. Such fragments will typically comprise a domain or motif of a variant protein of the present invention, e.g., active site, transmembrane domain, or ligand/substrate binding domain. Other fragments include, but are not limited to, domain or motif-containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known to those of skill in the art (e.g., PROSITE analysis). Current Protocols in Protein Science, John Wiley & Sons, N.Y. (2002).

Uses of Variant Proteins

The variant proteins of the present invention can be used in a variety of ways, including but not limited to, in assays to determine the biological activity of a variant protein, such as in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another type of immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the variant protein (or its binding partner) in biological fluids; as a marker for cells or tissues in which it is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); as a target for screening for a therapeutic agent; and as a direct therapeutic agent to be administered into a human subject. Any of the variant proteins disclosed herein may be developed into reagent grade or kit format for commercialization as research products. Methods for performing the uses listed above are well known to those skilled in the art. See, e.g., Molecular Cloning: A Laboratory Manual, Sambrook and Russell, Cold Spring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology: Guide to Molecular Cloning Techniques, S. L. Berger and A. R. Kimmel, eds., Academic Press (1987).

In a specific embodiment of the invention, the methods of the present invention include detection of one or more variant proteins disclosed herein. Variant proteins are disclosed in Table 1 and in the Sequence Listing as SEQ ID NOS:17-32. Detection of such proteins can be accomplished using, for example, antibodies, small molecule compounds, aptamers, ligands/substrates, other proteins or protein fragments, or other protein-binding agents. Preferably, protein detection agents are specific for a variant protein of the present invention and can therefore discriminate between a variant protein of the present invention and the wild-type protein or another variant form. This can generally be accomplished by, for example, selecting or designing detection agents that bind to the region of a protein that differs between the variant and wild-type protein, such as a region of a protein that contains one or more amino acid substitutions that is/are encoded by a non-synonymous cSNP of the present invention, or a region of a protein that follows a nonsense mutation-type SNP that creates a stop codon thereby leading to a shorter polypeptide, or a region of a protein that follows a read-through mutation-type SNP that destroys a stop codon thereby leading to a longer polypeptide in which a portion of the polypeptide is present in one version of the polypeptide but not the other.

In another specific aspect of the invention, the variant proteins of the present invention are used as targets for diagnosing or prognosing autoimmune disease or for determining predisposition to autoimmune disease in a human, for treating and/or preventing autoimmune disease, or for predicting an individual's response to TNF inhibitor treatment (particularly treatment or prevention of autoimmune disease using TNF inhibitors), etc. Accordingly, the invention provides methods for detecting the presence of, or levels of, one or more variant proteins of the present invention in a cell, tissue, or organism. Such methods typically involve contacting a test sample with an agent (e.g., an antibody, small molecule compound, or peptide) capable of interacting with the variant protein such that specific binding of the agent to the variant protein can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an array, for example, an antibody or aptamer array (arrays for protein detection may also be referred to as “protein chips”). The variant protein of interest can be isolated from a test sample and assayed for the presence of a variant amino acid sequence encoded by one or more SNPs disclosed by the present invention. The SNPs may cause changes to the protein and the corresponding protein function/activity, such as through non-synonymous substitutions in protein coding regions that can lead to amino acid substitutions, deletions, insertions, and/or rearrangements; formation or destruction of stop codons; or alteration of control elements such as promoters. SNPs may also cause inappropriate post-translational modifications.

One preferred agent for detecting a variant protein in a sample is an antibody capable of selectively binding to a variant form of the protein (antibodies are described in greater detail in the next section). Such samples include, for example, tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.

In vitro methods for detection of the variant proteins associated with autoimmune disease that are disclosed herein and fragments thereof include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), Western blots, immunoprecipitations, immunofluorescence, and protein arrays/chips (e.g., arrays of antibodies or aptamers). For further information regarding immunoassays and related protein detection methods, see Current Protocols in Immunology, John Wiley & Sons, N.Y., and Hage, “Immunoassays,” Anal Chem 15; 71(12):294R-304R (June 1999).

Additional analytic methods of detecting amino acid variants include, but are not limited to, altered electrophoretic mobility, altered tryptic peptide digest, altered protein activity in cell-based or cell-free assay, alteration in ligand or antibody-binding pattern, altered isoelectric point, and direct amino acid sequencing.

Alternatively, variant proteins can be detected in vivo in a subject by introducing into the subject a labeled antibody (or other type of detection reagent) specific for a variant protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based on the class or action of the protein. For example, proteins isolated from humans and their mammalian orthologs serve as targets for identifying agents (e.g., small molecule drugs or antibodies) for use in therapeutic applications, particularly for modulating a biological or pathological response in a cell or tissue that expresses the protein. Pharmaceutical agents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compounds can be developed that modulate protein function. For example, many SNPs disclosed herein affect the amino acid sequence of the encoded protein (e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Such alterations in the encoded amino acid sequence may affect protein function, particularly if such amino acid sequence variations occur in functional protein domains, such as catalytic domains, ATP-binding domains, or ligand/substrate binding domains. It is well established in the art that variant proteins having amino acid sequence variations in functional domains can cause or influence pathological conditions. In such instances, compounds (e.g., small molecule drugs or antibodies) can be developed that target the variant protein and modulate (e.g., up- or down-regulate) protein function/activity.

The therapeutic methods of the present invention further include methods that target one or more variant proteins of the present invention. Variant proteins can be targeted using, for example, small molecule compounds, antibodies, aptamers, ligands/substrates, other proteins, or other protein-binding agents. Additionally, the skilled artisan will recognize that the novel protein variants (and polymorphic nucleic acid molecules) disclosed in Table 1 may themselves be directly used as therapeutic agents by acting as competitive inhibitors of corresponding art-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can utilize cells that naturally express the protein, a biopsy specimen, or cell cultures. In one embodiment, cell-based assays involve recombinant host cells expressing the variant protein. Cell-free assays can be used to detect the ability of a compound to directly bind to a variant protein or to the corresponding SNP-containing nucleic acid fragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriate fragments thereof, can be used in high-throughput screening assays to test candidate compounds for the ability to bind and/or modulate the activity of the variant protein. These candidate compounds can be further screened against a protein having normal function (e.g., a wild-type/non-variant protein) to further determine the effect of the compound on the protein activity. Furthermore, these compounds can be tested in animal or invertebrate systems to determine in vivo activity/effectiveness. Compounds can be identified that activate (agonists) or inactivate (antagonists) the variant protein, and different compounds can be identified that cause various degrees of activation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for the ability to stimulate or inhibit interaction between the variant protein and a target molecule that normally interacts with the protein. The target can be a ligand, a substrate or a binding partner that the protein normally interacts with (for example, epinephrine or norepinephrine). Such assays typically include the steps of combining the variant protein with a candidate compound under conditions that allow the variant protein, or fragment thereof, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the variant protein and the target, such as any of the associated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab′)₂, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).

One candidate compound is a soluble fragment of the variant protein that competes for ligand binding. Other candidate compounds include mutant proteins or appropriate fragments containing mutations that affect variant protein function and thus compete for ligand. Accordingly, a fragment that competes for ligand, for example with a higher affinity, or a fragment that binds ligand but does not allow release, is encompassed by the invention.

The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) variant protein activity. The assays typically involve an assay of events in the signal transduction pathway that indicate protein activity. Thus, the expression of genes that are up or down-regulated in response to the variant protein dependent signal cascade can be assayed. In one embodiment, the regulatory region of such genes can be operably linked to a marker that is easily detectable, such as luciferase. Alternatively, phosphorylation of the variant protein, or a variant protein target, could also be measured. Any of the biological or biochemical functions mediated by the variant protein can be used as an endpoint assay. These include all of the biochemical or biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art.

Binding and/or activating compounds can also be screened by using chimeric variant proteins in which an amino terminal extracellular domain or parts thereof, an entire transmembrane domain or subregions, and/or the carboxyl terminal intracellular domain or parts thereof, can be replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than that which is normally recognized by a variant protein. Accordingly, a different set of signal transduction components is available as an end-point assay for activation. This allows for assays to be performed in other than the specific host cell from which the variant protein is derived.

The variant proteins are also useful in competition binding assays in methods designed to discover compounds that interact with the variant protein. Thus, a compound can be exposed to a variant protein under conditions that allow the compound to bind or to otherwise interact with the variant protein. A binding partner, such as ligand, that normally interacts with the variant protein is also added to the mixture. If the test compound interacts with the variant protein or its binding partner, it decreases the amount of complex formed or activity from the variant protein. This type of assay is particularly useful in screening for compounds that interact with specific regions of the variant protein. Hodgson, Bio/technology, 10(9), 973-80 (September 1992).

To perform cell-free drug screening assays, it is sometimes desirable to immobilize either the variant protein or a fragment thereof, or its target molecule, to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Any method for immobilizing proteins on matrices can be used in drug screening assays. In one embodiment, a fusion protein containing an added domain allows the protein to be bound to a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g., ³⁵S-labeled) and a candidate compound, such as a drug candidate, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads can be washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of bound material found in the bead fraction quantitated from the gel using standard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Alternatively, antibodies reactive with the variant protein but which do not interfere with binding of the variant protein to its target molecule can be derivatized to the wells of the plate, and the variant protein trapped in the wells by antibody conjugation. Preparations of the target molecule and a candidate compound are incubated in the variant protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the protein target molecule, or which are reactive with variant protein and compete with the target molecule, and enzyme-linked assays that rely on detecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the protein pathway, such as autoimmune disease. These methods of treatment typically include the steps of administering the modulators of protein activity in a pharmaceutical composition to a subject in need of such treatment.

The variant proteins, or fragments thereof, disclosed herein can themselves be directly used to treat a disorder characterized by an absence of, inappropriate, or unwanted expression or activity of the variant protein. Accordingly, methods for treatment include the use of a variant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as “bait proteins” in a two-hybrid assay or three-hybrid assay to identify other proteins that bind to or interact with the variant protein and are involved in variant protein activity. See, e.g., U.S. Pat. No. 5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J Biol Chem 268:12046-12054 (1993); Bartel et al., Biotechniques 14:920-924 (1993); Iwabuchi et al., Oncogene 8:1693-1696 (1993); and Brent, WO 94/10300. Such variant protein-binding proteins are also likely to be involved in the propagation of signals by the variant proteins or variant protein targets as, for example, elements of a protein-mediated signaling pathway. Alternatively, such variant protein-binding proteins are inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of most transcription factors, which typically consist of separable DNA-binding and activation domains. Briefly, the assay typically utilizes two different DNA constructs. In one construct, the gene that codes for a variant protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a variant protein-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected, and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein that interacts with the variant protein.

Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind to the variant proteins disclosed herein and fragments thereof. Such antibodies may be used to quantitatively or qualitatively detect the variant proteins of the present invention. As used herein, an antibody selectively binds a target variant protein when it binds the variant protein and does not significantly bind to non-variant proteins, i.e., the antibody does not significantly bind to normal, wild-type, or art-known proteins that do not contain a variant amino acid sequence due to one or more SNPs of the present invention (variant amino acid sequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPs that create a stop codon, thereby causing a truncation of a polypeptide or SNPs that cause read-through mutations resulting in an extension of a polypeptide).

As used herein, an antibody is defined in terms consistent with that recognized in the art: they are multi-subunit proteins produced by an organism in response to an antigen challenge. The antibodies of the present invention include both monoclonal antibodies and polyclonal antibodies, as well as antigen-reactive proteolytic fragments of such antibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, an antibody of the present invention further includes any of a variety of engineered antigen-binding molecules such as a chimeric antibody (U.S. Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc Natl Acad Sci USA 81:6851 (1984); Neuberger et al., Nature 312:604 (1984)), a humanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089 and 5,565,332), a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544 (1989)), a bispecific antibody with two binding specificities (Segal et al., J Immunol Methods 248:1 (2001); Carter, J Immunol Methods 248:7 (2001)), a diabody, a triabody, and a tetrabody (Todorovska et al., J Immunol Methods 248:47 (2001)), as well as a Fab conjugate (dimer or trimer), and a minibody.

Many methods are known in the art for generating and/or identifying antibodies to a given target antigen. Harlow, Antibodies, Cold Spring Harbor Press, N.Y. (1989). In general, an isolated peptide (e.g., a variant protein of the present invention) is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit, hamster or mouse. Either a full-length protein, an antigenic peptide fragment (e.g., a peptide fragment containing a region that varies between a variant protein and a corresponding wild-type protein), or a fusion protein can be used. A protein used as an immunogen may be naturally-occurring, synthetic or recombinantly produced, and may be administered in combination with an adjuvant, including but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substance such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology, which immortalizes cells secreting a specific monoclonal antibody. Kohler and Milstein, Nature 256:495 (1975). The immortalized cell lines can be created in vitro by fusing two different cell types, typically lymphocytes, and tumor cells. The hybridoma cells may be cultivated in vitro or in vivo. Additionally, fully human antibodies can be generated by transgenic animals. He et al., J Immunol 169:595 (2002). Fd phage and Fd phagemid technologies may be used to generate and select recombinant antibodies in vitro. Hoogenboom and Chames, Immunol Today 21:371 (2000); Liu et al., J Mol Biol 315:1063 (2002). The complementarity-determining regions of an antibody can be identified, and synthetic peptides corresponding to such regions may be used to mediate antigen binding. U.S. Pat. No. 5,637,677.

Antibodies are preferably prepared against regions or discrete fragments of a variant protein containing a variant amino acid sequence as compared to the corresponding wild-type protein (e.g., a region of a variant protein that includes an amino acid encoded by a nonsynonymous cSNP, a region affected by truncation caused by a nonsense SNP that creates a stop codon, or a region resulting from the destruction of a stop codon due to read-through mutation caused by a SNP). Furthermore, preferred regions will include those involved in function/activity and/or protein/binding partner interaction. Such fragments can be selected on a physical property, such as fragments corresponding to regions that are located on the surface of the protein, e.g., hydrophilic regions, or can be selected based on sequence uniqueness, or based on the position of the variant amino acid residue(s) encoded by the SNPs provided by the present invention. An antigenic fragment will typically comprise at least about 8-10 contiguous amino acid residues in which at least one of the amino acid residues is an amino acid affected by a SNP disclosed herein. The antigenic peptide can comprise, however, at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) or more amino acid residues, provided that at least one amino acid is affected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated by coupling (i.e., physically linking) the antibody or an antigen-reactive fragment thereof to a detectable substance. Detectable substances include, but are not limited to, various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies, particularly the use of antibodies as therapeutic agents, are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,” Expert Rev Vaccines (1):53-9 (February 2003); Ross et al., “Anticancer antibodies,” Am J Clin Pathol 119(4):472-85 (April 2003); Goldenberg, “Advancing role of radiolabeled antibodies in the therapy of cancer,” Cancer Immunol Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003; Ross et al., “Antibody-based therapeutics in oncology,” Expert Rev Anticancer Ther 3(1):107-21 (February 2003); Cao et al., “Bispecific antibody conjugates in therapeutics,” Adv Drug Deliv Rev 55(2):171-97 (February 2003); von Mehren et al., “Monoclonal antibody therapy for cancer,” Annu Rev Med 54:343-69 (2003); Epub Dec. 3, 2001; Hudson et al., “Engineered antibodies,” Nat Med 9(1):129-34 (January 2003); Brekke et al., “Therapeutic antibodies for human diseases at the dawn of the twenty-first century,” Nat Rev Drug Discov 2(1):52-62 (January 2003); Erratum in: Nat Rev Drug Discov 2(3):240 (March 2003); Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Andreakos et al., “Monoclonal antibodies in immune and inflammatory diseases,” Curr Opin Biotechnol 13(6):615-20 (December 2002); Kellermann et al., “Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics,” Curr Opin Biotechnol 13(6):593-7 (December 2002); Pini et al., “Phage display and colony filter screening for high-throughput selection of antibody libraries,” Comb Chem High Throughput Screen 5(7):503-10 (November 2002); Batra et al., “Pharmacokinetics and biodistribution of genetically engineered antibodies,” Curr Opin Biotechnol 13(6):603-8 (December 2002); and Tangri et al., “Rationally engineered proteins or antibodies with absent or reduced immunogenicity,” Curr Med Chem 9(24):2191-9 (December 2002).

Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the present invention from a natural cell source or from recombinant host cells by standard techniques, such as affinity chromatography or immunoprecipitation. In addition, antibodies are useful for detecting the presence of a variant protein of the present invention in cells or tissues to determine the pattern of expression of the variant protein among various tissues in an organism and over the course of normal development or disease progression. Further, antibodies can be used to detect variant protein in situ, in vitro, in a bodily fluid, or in a cell lysate or supernatant in order to evaluate the amount and pattern of expression. Also, antibodies can be used to assess abnormal tissue distribution, abnormal expression during development, or expression in an abnormal condition, such as in autoimmune disease, or during TNF inhibitor treatment. Additionally, antibody detection of circulating fragments of the full-length variant protein can be used to identify turnover.

Antibodies to the variant proteins of the present invention are also useful in pharmacogenomic analysis. Thus, antibodies against variant proteins encoded by alternative SNP alleles can be used to identify individuals that require modified treatment modalities.

Further, antibodies can be used to assess expression of the variant protein in disease states such as in active stages of the disease or in an individual with a predisposition to a disease related to the protein's function, such as autoimmune disease, or during the course of a treatment regime, such as during TNF inhibitor treatment. Antibodies specific for a variant protein encoded by a SNP-containing nucleic acid molecule of the present invention can be used to assay for the presence of the variant protein, such as to diagnose or prognose autoimmune disease or to predict an individual's response to TNF inhibitor treatment or predisposition/susceptibility to autoimmune disease, as indicated by the presence of the variant protein.

Antibodies are also useful as diagnostic tools for evaluating the variant proteins in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specific variant protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.

Antibodies can also be used to assess aberrant subcellular localization of a variant protein in cells in various tissues. The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting the expression level or the presence of variant protein or aberrant tissue distribution or developmental expression of a variant protein, antibodies directed against the variant protein or relevant fragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function, for example, by blocking the binding of a variant protein to a binding partner. These uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be used, for example, to block or competitively inhibit binding, thus modulating (agonizing or antagonizing) the activity of a variant protein. Antibodies can be prepared against specific variant protein fragments containing sites required for function or against an intact variant protein that is associated with a cell or cell membrane. For in vivo administration, an antibody may be linked with an additional therapeutic payload such as a radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent. Suitable cytotoxic agents include, but are not limited to, bacterial toxin such as diphtheria, and plant toxin such as ricin. The in vivo half-life of an antibody or a fragment thereof may be lengthened by pegylation through conjugation to polyethylene glycol. Leong et al., Cytokine 16:106 (2001).

The invention also encompasses kits for using antibodies, such as kits for detecting the presence of a variant protein in a test sample. An exemplary kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample; means for determining the amount, or presence/absence of variant protein in the sample; means for comparing the amount of variant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing the SNP-containing nucleic acid molecules described herein. The term “vector” refers to a vehicle, preferably a nucleic acid molecule, which can transport a SNP-containing nucleic acid molecule. When the vector is a nucleic acid molecule, the SNP-containing nucleic acid molecule can be covalently linked to the vector nucleic acid. Such vectors include, but are not limited to, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the SNP-containing nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the SNP-containing nucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the SNP-containing nucleic acid molecules. The vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions that are operably linked in the vector to the SNP-containing nucleic acid molecules such that transcription of the SNP-containing nucleic acid molecules is allowed in a host cell. The SNP-containing nucleic acid molecules can also be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the SNP-containing nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.

The regulatory sequences to which the SNP-containing nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.

In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region, a ribosome-binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. A person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors. See, e.g., Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

A variety of expression vectors can be used to express a SNP-containing nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example, vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors can also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g., cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The regulatory sequence in a vector may provide constitutive expression in one or more host cells (e.g., tissue specific expression) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor, e.g., a hormone or other ligand. A variety of vectors that provide constitutive or inducible expression of a nucleic acid sequence in prokaryotic and eukaryotic host cells are well known to those of ordinary skill in the art.

A SNP-containing nucleic acid molecule can be inserted into the vector by methodology well-known in the art. Generally, the SNP-containing nucleic acid molecule that will ultimately be expressed is joined to an expression vector by cleaving the SNP-containing nucleic acid molecule and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.

The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial host cells include, but are not limited to, Escherichia coli, Streptomyces spp., and Salmonella typhimurium. Eukaryotic host cells include, but are not limited to, yeast, insect cells such as Drosophila spp., animal cells such as COS and CHO cells, and plant cells.

As described herein, it may be desirable to express the variant peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the variant peptides. Fusion vectors can, for example, increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting, for example, as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired variant peptide can ultimately be separated from the fusion moiety. Proteolytic enzymes suitable for such use include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein (S. Gottesman, Gene Expression Technology: Methods in Enzymology 185:119-128, Academic Press, Calif. (1990)). Alternatively, the sequence of the SNP-containing nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example, E. coli. Wada et al., Nucleic Acids Res 20:2111-2118 (1992).

The SNP-containing nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari et al., EMBO J 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943 (1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., Mol Cell Biol 3:2156-2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (B. Seed, Nature 329:840 (1987)) and pMT2PC (Kaufman et al., EMBO J. 6:187-195 (1987)).

The invention also encompasses vectors in which the SNP-containing nucleic acid molecules described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to the SNP-containing nucleic acid sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.

The recombinant host cells can be prepared by introducing the vector constructs described herein into the cells by techniques readily available to persons of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, N.Y. (2000).

Host cells can contain more than one vector. Thus, different SNP-containing nucleotide sequences can be introduced in different vectors into the same cell. Similarly, the SNP-containing nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the SNP-containing nucleic acid molecules, such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced, or joined to the nucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication can occur in host cells that provide functions that complement the defects.

Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be inserted in the same vector that contains the SNP-containing nucleic acid molecules described herein or may be in a separate vector. Markers include, for example, tetracycline or ampicillin-resistance genes for prokaryotic host cells, and dihydrofolate reductase or neomycin resistance genes for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait can be effective.

While the mature variant proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these variant proteins using RNA derived from the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as G-protein-coupled receptors (GPCRs), appropriate secretion signals can be incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the protein can be isolated from the host cell by standard disruption procedures, including freeze/thaw, sonication, mechanical disruption, use of lysing agents, and the like. The variant protein can then be recovered and purified by well-known purification methods including, for example, ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.

It is also understood that, depending upon the host cell in which recombinant production of the variant proteins described herein occurs, they can have various glycosylation patterns, or may be non-glycosylated, as when produced in bacteria. In addition, the variant proteins may include an initial modified methionine in some cases as a result of a host-mediated process.

For further information regarding vectors and host cells, see Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins described herein have a variety of uses. For example, the cells are useful for producing a variant protein that can be further purified into a preparation of desired amounts of the variant protein or fragments thereof. Thus, host cells containing expression vectors are useful for variant protein production.

Host cells are also useful for conducting cell-based assays involving the variant protein or variant protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a variant protein is useful for assaying compounds that stimulate or inhibit variant protein function. Such an ability of a compound to modulate variant protein function may not be apparent from assays of the compound on the native/wild-type protein, or from cell-free assays of the compound. Recombinant host cells are also useful for assaying functional alterations in the variant proteins as compared with a known function.

Genetically-engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a non-human mammal, for example, a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA containing a SNP of the present invention which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more of its cell types or tissues. Such animals are useful for studying the function of a variant protein in vivo, and identifying and evaluating modulators of variant protein activity. Other examples of transgenic animals include, but are not limited to, non-human primates, sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-human mammals such as cows and goats can be used to produce variant proteins which can be secreted in the animal's milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containing nucleic acid molecule into the male pronuclei of a fertilized oocyte, e.g., by microinjection or retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any nucleic acid molecules that contain one or more SNPs of the present invention can potentially be introduced as a transgene into the genome of a non-human animal.

Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the variant protein in particular cells or tissues.

Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al.; U.S. Pat. No. 4,873,191 by Wagner et al., and in B. Hogan, Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, N.Y. (1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes a non-human animal in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.

In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. Lakso et al., PNAS 89:6232-6236 (1992). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae. O'Gorman et al., Science 251:1351-1355 (1991). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are generally needed. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected variant protein and the other containing a transgene encoding a recombinase.

Clones of the non-human transgenic animals described herein can also be produced according to the methods described, for example, in I. Wilmut et al., Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G_(o) phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell (e.g., a somatic cell) is isolated.

Transgenic animals containing recombinant cells that express the variant proteins described herein are useful for conducting the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could influence ligand or substrate binding, variant protein activation, signal transduction, or other processes or interactions, may not be evident from in vitro cell-free or cell-based assays. Thus, non-human transgenic animals of the present invention may be used to assay in vivo variant protein function as well as the activities of a therapeutic agent or compound that modulates variant protein function/activity or expression. Such animals are also suitable for assessing the effects of null mutations (i.e., mutations that substantially or completely eliminate one or more variant protein functions).

For further information regarding transgenic animals, see Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Petters et al., “Transgenic animals as models for human disease,” Transgenic Res 9(4-5):347-51, discussion 345-6 (2000); Wolf et al., “Use of transgenic animals in understanding molecular mechanisms of toxicity,” J Pharm Pharmacol 50(6):567-74 (June 1998); Echelard, “Recombinant protein production in transgenic animals,” Curr Opin Biotechnol 7(5):536-40 (October 1996); Houdebine, “Transgenic animal bioreactors,” Transgenic Res 9(4-5):305-20 (2000); Pirity et al., “Embryonic stem cells, creating transgenic animals,” Methods Cell Biol 57:279-93 (1998); and Robl et al., “Artificial chromosome vectors and expression of complex proteins in transgenic animals,” Theriogenology 59(1):107-13 (January 2003).

EXAMPLES

The following examples are offered to illustrate, but not limit, the claimed invention.

Example 1 Analysis of SNPs Associated with Rheumatoid Arthritis

Overview

A multi-tiered, case-control association study was carried out in which 25,966 putative functional SNPs were genotyped in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands). A SNP, rs1953126, on chromosome 9q33.2 was identified that was significantly associated with RA (OR_(common)=1.28, trend P_(comb)=1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P_(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the 5′ end of PHF19 across TRAF1 into the TRAF1-05 intergenic region, but excluding the C5 coding region, as the most significant (trend P_(comb): 1.45E-06→5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Furthermore, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.

Thus, variants in the PHF19-TRAF1-05 region on chromosome 9q33.2 are disclosed herein that show strong and consistent association across three independent RA case-control studies (1732 cases/2502 controls). Combining genetic information from HLA, PTPN22 and TRAF1 variants, the posterior probability of RA was calculated for every possible genotype combination. These variants have utilities for such uses as individualized prognosis and targeted medicine.

See Chang et al., “A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2”, PLoS Genet. 2008 Jun. 27; 4(6):e1000107, incorporated herein by reference in its entirety.

Results

Identification of the RA-Associated Chr9q33.2-Region

Three sequential case-control studies were conducted to identify SNPs associated with RA. In the first study, DNA samples from white North Americans with (N=475 cases) and without (N=475 controls) RA (sample set 1, see Table 8 for a breakdown of the clinical characteristics of each sample set) were genotyped for a set of 25,966 gene-centric SNPs utilizing disease-phenotype-based pooled DNA samples (pooled DNA samples were used to increase genotyping throughput while minimizing DNA consumption). The allele frequency of each SNP was determined in cases and controls as described in the “Materials and Methods” section of Example 1 below and 1438 SNPs were significantly associated with RA using an allelic test (P<0.05); 88 of these SNPs mapped to chr 6p21 between HLA-F and HLA-DPB1 within the major histocompatibility complex (MHC). Of the 1350 non-MHC SNPs, 1306 were evaluated in a second independent white North American sample set (661 cases and 1322 controls) by use of a similar pooling strategy (44 SNPs were not genotyped due to insufficient primer quantities). Eighty-nine statistically compelling SNPs (P_(allelic)<0.05) with the same risk allele in these two sample sets were then individually genotyped in sample set 1 to verify the results from the pooled DNA phase of the experiment; 55 SNPs retained statistical significance (P_(allelic)<0.05) and 44 have been individually genotyped in sample set 2. Twenty-eight of these were significant (P_(allelic)<0.05) and are currently being evaluated in a third independent white Dutch sample set (596 cases and 705 controls).

The most significant non-MHC SNP to emerge from a combined analysis of sample sets 1 and 2 after the PTPN22 missense SNP, rs2476601 [9], was rs1953126, which is an intergenic SNP located 1 kb upstream of the human homologue to the Drosophila polycomblike protein-encoding gene, PHF19, on chr 9q33.2 near two candidate genes, TRAF1 and CS (individual genotyping: Sample Set 1: OR=1.30, 95% CI 1.08-1.58, trend P=0.007; Sample Set 2: OR=1.35, 95% CI 1.18-1.56, trend P=1.69E-05). This SNP was also genotyped in sample set 3 (association: OR=1.16, 95% CI 0.99-1.36, trend P=0.066) (Tables 5-7). No significant deviations from Hardy-Weinberg equilibrium were observed for the genotypes of this SNP in the cases or controls in the three sample sets. The frequency of the minor allele was approximately 30.8% in white North American controls and increasing to 37.3% in white North American cases, and 34.9% in Dutch controls and increasing to 38.3% in Dutch cases. A combined analysis across all three sample sets was highly significant (OR=1.28, 95% CI 1.16-1.40, trend P_(comb)=1.45E-06).

Chr 9q33.2 Fine-Mapping and LD Analyses

To further explore the association signal in this region, patterns of LD from the CEU HapMap data [36] were used to define a broad 668 kb region, extending from MEGF9 to STOM on chr9q33.2, for follow-up individual genotyping. Postulating two different disease models, one where the originally identified SNP, rs1953126, was in LD with one or more causative SNPs and a second model of allelic heterogeneity where several alleles at a locus independently predispose individuals to disease, a combination of 137 LD and tagging SNPs were selected from this region for follow-up genotyping in Sample Set 1 (a detailed description of SNP selection is outlined in the “Materials and Methods” section of Example 1 below). Only four SNPs, all in the RAB14-GSN-STOM region, were mildly out of Hardy-Weinberg equilibrium (10⁻⁴<P<0.01) in the controls (Tables 5-7). Including the original SNP, rs1953126, 38 of the 138 chr9q33.2-region SNPs genotyped in Sample Set 1 were significant at the 0.01 level.

To better understand these positive signals and select a subset of informative SNPs for genotyping in the other sample sets, the LD architecture around rs1953126 was investigated by calculating pairwise r² values for all 138 SNPs genotyped in Sample Set 1. Evaluating cases and controls separately revealed very similar LD patterns between both groups across this region. There were two primary haplotype blocks (LD Block 1 and LD Block 2) (here an LD block is defined as a region in which over 75% of all pairwise r² LD correlation values exceeded 0.3), with moderate LD between pairs of SNPs residing within each of the two blocks. LD Block 1, which contains the original SNP, rs1953126, and is approximately 70 kb, extends from rs10985070, an intronic SNP in the 5′ end of PHF19, across TRAF1 into the TRAF1-05 intergenic region to rs2900180. Approximately 214 kb in length, LD Block 2 ranges from the middle of C5 to the RAB14-GSN intergenic region. Given that haplotype block structures can have complex LD patterns within and between blocks and that a single associated SNP in this region (rs1953126) was focused on, a higher resolution plot was generated (not shown) where pairwise r² values were calculated for rs1953126 and each of the remaining 137 SNPs, which revealed groups of highly correlated SNPs not readily visible in the LD heat-map.

Integrating the Sample Set 1 association results with the LD measures, it was found that the original SNP, rs1953126, was highly correlated (r²>0.95) with 17 other SNPs in LD Block 1. These 17 other “Group 1” SNPs in LD Block 1 (in addition to rs1953126) are as follows: rs1609810, rs7034390, rs2270231, rs881375, rs6478486, rs1860824, rs10435844, rs2239657, rs2239658, rs2416805, rs876445, rs7021206, rs1014529, rs1930781, rs2416806, rs7864019, and rs2900180 (additionally, the following SNPs, all of which lie in LD Block 1 between rs10985070 and rs2900180, were not genotyped but highly correlated (r²>0.90) with Group 1 SNPs in the CEU HapMap data: rs1930778, rs10760121, rs1468671, rs7046108, rs10435843, rs758959, rs2109895, rs1930780, rs10739580, rs10733648, and rs7039505). These 18 SNPs (the 17 SNPs above plus rs1953126) have similar association results increasing in frequency from approximately 30-31% in controls to 36-37% in cases (OR=1.29-1.35, trend P˜0.002-0.009) (Tables 5-7). It was observed that 20 non-Group 1 SNPs were associated with disease at equal or greater significance including 14 other SNPs from LD Block 1. Thirteen of these other LD Block 1 SNPs, which were highly correlated with one another (r²>0.95) and reasonably correlated with the Group 1 SNPs (r²=0.66-0.72), had minor allele frequencies of approximately 38% in controls, increasing to 46% in cases (OR=1.34-1.39, trend P≦0.002). These 13 “Group 2” SNPs are as follows: rs10985070, rs10985073, rs10818482, rs2072438, rs10760126, rs4836834, rs2416804, rs10118357, rs7021049, rs1930782, rs3761846, rs10760130, and rs10818488 (additionally, the following SNPs, all of which lie in LD Block 1 between rs10985070 and rs2900180, were not genotyped but highly correlated (r²>0.90) with Group 2 SNPs in the CEU HapMap data: rs2269060, rs7037195, rs1014530, rs3761847, and rs10760129). The fourteenth significant SNP in LD Block 1, rs7021880, a TRAF1 intronic SNP, was also highly significant (OR=1.43, trend P=3.12E-04), increasing in frequency from 27.1% in controls to 34.7% in cases. This SNP was in LD with both the Group 1 (r²=0.82-0.90) and the Group 2 SNPs (r²=0.59-0.64) SNPs. The six other SNPs with P values <0.01 lie upstream of LD Block 1 (n=4) or downstream of LD Block 2 in GSN (n=2) (Tables 5-7). The PSMD5 intronic SNP, rs10760117, was particularly significant among these six SNPs.

Given the association results and the LD structure, 72 of the 137 fine-scale mapping SNPs were selected to genotype in Sample Set 2 (661 white North American RA patients and 1322 matched white North American controls) (Tables 5-7). This subset of fine-scale mapping SNPs was chosen to reduce the genotyping load, while capturing the association signals and retaining full coverage of the genetic variation in this region. Two of these 72 SNPs, rs12683062 (in CEP110) in the cases and rs9409230 (a RAB14-GSN intergenic SNP) in the controls, were moderately out of Hardy-Weinberg equilibrium (P=2.56E-04 and P=0.003, respectively; Tables 5-7). Including the original SNP, rs1953126, 23 of these 72 SNPs were significant (trend P<0.01) in Sample Set 2; however, the nine significant LD Block 1 SNPs in Sample Set 1 were the most significant, replicated SNPs in Sample Set 2. There were three SNPs in GSN (rs10985196, rs7046030 and rs12683459), all highly correlated with pairwise r² values >0.90, which were highly significant (trend P<10⁻⁶) in Sample Set 2 (Sample Set 1: trend P=0.01-0.05).

Forty-two SNPs were genotyped in Sample Set 3 (596 white Dutch RA patients and 705 white Dutch controls); none of these SNPs rejected HWE at the P<0.01 significance level (Tables 5-7). These 42 SNPs span over 600 kb and were selected to cover genetic variability, association patterns and gene boundaries. Four of the 42 SNPs, spanning 286 kb from TRAF1 to RAB14, were significant at the 0.01 level. Of these four, two SNPs (rs4836834 and rs7021049) were members of Group 2 from LD Block 1, perfectly correlated (r²=1), and both SNPs were highly significant in all three sample sets. The six Group 1 SNPs genotyped in Sample Set 3 were close to the 0.05 significance level, with the most significant of these being the synonymous P340P TRAF1 SNP, rs2239657 and the TRAF1-05 intergenic SNP, rs2900180 (trend P=0.052) (Tables 5-7) (for the TRAF1 intronic SNP, rs7021880, trend P=0.102 in this sample set).

In a combined analysis of the 43 SNPs genotyped in all three sample sets, including the original SNP, rs1953126, 20 SNPs, spanning a region of over 525 kb from rs7026635 within FBXW2 to rs10818527 within GSN, were significantly associated with RA (trend P_(comb)<0.01) (Table 9). Several of these SNPs exhibited consistent and strong association across all three sample sets (Tables 5-7). Using either a combined trend or genotypic P-value, the top-ranked five SNPs were: rs6478486, rs4836834, rs2239657, rs7021880 and rs7021049 (listed in order of position). All reside within or near TRAF1 in LD Block 1, had common odds ratios of approximately 1.3, and were highly significant (trend P_(comb)<1.5E-07) (Table 9).

Multiple Testing

Since false-positive results can be problematic in any large-scale experiment in which modest nominal significance levels are used, the results from the combined analysis were corrected for multiple testing using the method of Dunn-Sidak [37]. Seven SNPS, all within LD Block 1, survived a Dunn-Sidak correction for 25,966 SNPs at P<0.01. The corrected trend P_(comb) values for the five most significant SNPs were: 0.003 for rs6478486 and 0.004 for rs223957 (Group 1), 0.002 for rs4836834 and 0.001 for rs7021049 (Group 2), and 1.4E-04 for rs7021880.

Haplotype Sliding Window

Given that the fine-scale-mapping SNPs cluster into various groups based on their pairwise r² values and that under many models haplotypes can be more informative than single-markers [38], the Haplo-Stats package [39] was used to run a 5-SNP sliding-window haplotype association analysis on the 43 SNPs genotyped in all three sample sets separately for each sample set and then the statistical evidence was combined across all three sample sets. The combined analysis revealed a 29 kb-wide maximum peak of global association for haplotypes comprised of alleles segregating at rs6478486-rs4836834-rs2239657-rs7021880-rs7021049 in LD Block 1 (P_(comb)=4.15E-08). This region ranges from 9 kb downstream of TRAF1 in the PHF19-TRAF1 intergenic region to intron 3 within TRAF1. The disease association evidence for this PHF19-TRAF1 region was particularly strong. Aside from this peak and a second highly significant peak in the TRAF1 region (P_(comb)=5.45E-08; rs2239657-rs7021880-rs7021049-rs2900180-rs2269066), a second region of significance was centered over the RAB14-GSN region (P=2.11E-06).

Haplotype Analyses of LD Block 1 Variants

The single marker and sliding window haplotype analyses pointed to LD Block 1 as harboring RA-associated SNPs. The TRAF1 intronic SNP, rs7021880, was the most significant SNP in Sample Sets 1 (trend P=3.12E-04) and 2 (trend P=5.09E-07) and in the combined analysis (trend P_(comb)=5.41E-09) (in the Dutch sample set, trend P=0.102). In the Dutch sample set, the Group 2 SNPs, rs4836834 and rs7021049, were the most significant (trend P=0.004 and 0.006, respectively) (Tables 5-7 and 9). These Group 2 SNPs ranked second in significance in Sample Set 1 and in the combined analysis while in Sample Set 2 they ranked third behind rs7021880 and the Group 1 SNPs.

Given these results, the haplotype structure of LD Block 1 was analyzed using a subset of the nine SNPs from this region genotyped in all three studies. Taking into account the LD structure, the following three SNPs were selected for these analyses: rs2239657, the P340P TRAF1 synonymous polymorphism (to represent the six Group 1 SNPs); rs7021049, a TRAF1 intronic SNP (to represent the two Group 2 SNPs); and rs7021880. Haplotype frequencies for these three SNPs were estimated using the Haplo.Stats package [39], revealing the same four common haplotypes in each study (Table 10). Two of these haplotypes, AGT and GCG, were strongly associated with disease (P_(comb)=3.08E-08 and 8.00E-09, respectively), with the former being protective—decreasing in frequency from ˜60.9% in North American controls to 53.8% in North American cases and 56.7% in Dutch controls to 51.2% in Dutch cases (OR_(common)=0.76, 95% CI 0.70-0.83); and the latter being susceptible—increasing from 27.0% in North American controls to 34.7% in North American cases and from 33.2% in Dutch controls to 36.0% in Dutch cases (OR_(common)=1.32, 95% CI 1.21-1.45). These haplotype P_(comb)-values were not significantly different from those calculated for the individual SNPs (Table 9).

Dosage Effects

To explore the effect of the number of copies of each haplotype at these three sites (rs2239657, rs7021880 and rs7021049) along with any dominant/recessive effects between haplotypes, diplotypes were estimated using the pseudo-Gibbs sampling algorithm from the program SNPAnalyzer [40]. Analyzing the diplotypes individually, two diplotype combinations achieved statistical significance (P<0.01) when compared to all other diplotypes (Table 11). The AGT/AGT diplotype was strongly associated with protection against RA (P_(comb)=5.35E-07; OR_(common)=0.68, 95% CI 0.59-0.78), whereas the less frequent GCG/GCG diplotype was associated with predisposition (P_(comb)=0.005; OR_(common)=1.42, 95% CI 1.16-1.75).

Assuming a disease prevalence of 1%, the relative risk of RA was calculated in those individuals carrying two copies of the protective AGT haplotype compared to those without the AGT haplotype (RR_(2 copies AGT)=0.77). This homozygous relative risk was substantially reduced from the relative risk calculated from individuals carrying only one copy of the AGT haplotype (RR_(1 copy AGT)=1.06). Similarly, the relative risks for the susceptible GCG haplotype were estimated (RR_(2 copies GCG)=1.38; RR_(1 copy GCG)=1.15).

Genetic Background-Conditioned Results

A collection of 749 SNPs informative for European substructure was used to stratify both the cases and controls in Sample Set 2 [41]. By partitioning cases and controls into similar genetic background groups (“Northern European” or “Other”), the aim was to interrogate the data for strata-specific effects—that is, whether or not association signals were specific to one of these genetic background groups—and avoid potential confounding by population stratification. Although two SNPs demonstrated moderately higher significance levels following stratification—rs16910233 in C5 (P_(North)=0.019 compared to P_(unstrat)=0.147) and rs12685539 in CEP110 (P_(Other)=0.038 compared to P_(Unstrat)=0.115), a Breslow-Day test of effect heterogeneity comparing OR_(North) and OR_(Other) was not significant. Furthermore, a positional plot of Mantel-Haenszel P-values, testing for association given the genetic background stratification, was very similar to the unadjusted plot (not shown) suggesting that stratification of the case and control samples by SNPs informative for European substructure did not change the association patterns in Sample Set 2.

Rheumatoid Factor (RF)

Rheumatoid factor, a circulating antibody to immunoglobulin G, is a key serum analyte used in diagnosis of RA as well as an aid for the prognosis of RA-severity [2]. As the R620 W missense polymorphism in PTPN22 appears to have stronger susceptibility effects for RF-positive disease [9] and since RF is clinically important, the role of RF status on the chr 9q33.2 association patterns was investigated for the three LD Block 1 SNPs, rs2239657, rs7021880 and rs7021049, testing for both strata-specific effects as well as effect size differences between RF-positive and RF-negative disease.

To explore the effect isolated to RF-positive patients compared to controls, a strata-specific analysis was performed for all sample sets using a genotypic test. The resulting combined P-values for the RF-positive stratum were highly significant (P_(rs2239657)=4.02E-05, P_(rs7021880)=7.10E-06, P_(rs7021049)=5.68E-06; Table 12), which were slightly less significant when compared to the overall genotypic combined P-values (Table 9). A similar analysis of RF-negative disease in Sample Sets 2 and 3 yielded genotypic combined P-values of P_(rs2239657)=0.038, P_(rs7021880)=0.013, P_(rs7021049)=0.082. Allelic odds ratios and 95% confidence intervals were also calculated for each individual sample set and the results did not demonstrate a clear pattern of strata-specific effects within a stratum or differential effects between the two strata (Table 12). A Breslow-Day test was performed on Sample Set 2 (individually matched cases and controls) to formalize the test of homogeneity of odds ratios, showing that none of the three SNPs exhibited significant differential effects (Table 12). Similarly, results for the analogous Monte Carlo-based test performed in Sample Set 3 (where cases and controls were not individually matched) also did not reveal significant heterogeneity between RF-positive and RF-negative effects.

Logistic Regression

Logistic regression was used to further dissect association signals from LD patterns, build predictive models, and explore the relative effects of each SNP within the models constructed. To accomplish this, the number of SNPs for these analyses was first minimized by calculating pairwise r² values for the 43 SNPs genotyped in all three sample sets, and the SNPs were divided into distinct groups based on their LD structure. SNPs with pairwise r² values >0.90 were grouped together, resulting in 27 distinct groups (Table 13) and then the single most significant SNP from each group (P_(comb) from Table 9) was chosen for the logistic regression analyses.

In the univariate analysis, the TRAF1 intronic SNP rs7021049, which marks the Group 2 SNPs in LD Block 1, was the most significant SNP (P=1.24E-06), followed by rs7021880 (1.39E-06), and then the Group 1 SNP, rs2239657 (P=2.52E-06) (Table 13). In addition, 11 other SNPs were significant (P<0.01). To assess whether other observed associations in the region were primarily a result of LD with the most significant SNP, pairwise logistic regression was performed on all 27 SNPs, adjusting for rs7021049. One SNP retained statistical significance (P<0.01): rs10985196 (Group 21), a GSN intronic SNP (P=0.001). To test whether the combination of Group 2 and Group 21 variants fully accounted for the association with RA, the logistic regression was repeated, adjusting for both rs7021049 and rs10985196; none of the remaining groups of SNPs were significantly associated with RA.

To explore more complex models, both forwards and backwards stepwise logistic regression procedures were used separately on the same 27 SNPs in each individual sample set as well as in a combined analysis of all three sample sets (Table 14). The forward model for the combined samples, which included two SNPs, rs7021049 (the Group 2 TRAF1 intronic SNP) and rs10985196 (the GSN intronic SNP), was consistent with the results of the pairwise logistic regression analysis presented above.

Multi-Locus RA Risk Calculations

The risk of RA given genotypes at the three loci HLA-DRB1, PTPN22 and the TRAF1 region was estimated under three different possible unconditional RA risk assumptions (i.e., RA disease prevalence values) using Bayes' theorem. In total, there were 18 multi-locus genotype combinations, and RA risk was calculated for each combination using data from Sample Set 1 as described in the “Materials and Methods” section of Example 1 below. Assuming a 1% RA prevalence, similar to that observed in the white North American general population, the results indicate that individuals with the protective genotype at all three loci (0SE for HLA-DRB1, CC genotype for PTPN22 and the AGT/AGT TRAF1 diplotype) have a substantially reduced predicted risk of RA (0.29% vs. 1%), whereas those individuals in the highest-risk category (HLA-2SE, TT or TC genotype at PTPN22, and the GCG/GCG TRAF1 diplotype), have an estimated RA risk of 13.06%, representing more than a 45-fold increase in risk. These data are presented as a 3-D plot in FIG. 1 where the lowest risk value has been reset to 1 and the other values normalized accordingly. Approximately 19% of the general population will find themselves in the low-risk multi-locus genotype category and only 0.06% in the high risk group. In contrast, when the disease prevalence is increased to 30%, as might be observed in high-risk groups such as an early arthritis clinic, the range of risk drops to 7.88-fold, with the posterior probability of RA calculated to be 11% for the lowest-risk genotype combination and increasing to 86.4% in the highest risk category (Table 15).

Discussion

A large-scale, multi-tiered association study of RA was carried out using a panel of putative functional SNPs, particularly focuses on variants in the chromosome 9q33.2 region. In particular, three groups of SNPs, represented by rs2239657 (Group 1), rs7021049 (Group 2) and rs7021880 were highly significant and showed a localized effect to a 70 kb region extending from rs10985070, in intron 3 of PHF19, across TRAF1 to rs2900180 in the TRAF1-05 intergenic region, but excluding the C5 coding region (LD Block 1). Examination of the CEU HapMap data identified 16 additional SNPs (rs1930778, rs10760121, rs1468671, rs7046108, rs10435843, rs758959, rs2109895, rs1930780, rs10739580, rs10733648, rs7039505, rs2269060, rs7037195, rs1014530, rs3761847, rs10760129) that were highly correlated (r²>0.95) with either the Group 1 or Group 2 SNPs genotyped in this study, and all 16 fall within this 70 kb region. Across sample sets, the evidence for association at these sites was stronger, maintaining statistical significance after correction for multiple testing, and more consistent than sites in neighboring regions. Additional analyses further buttressed the statistical support for these conclusions: (i) a haplotype sliding window analysis of all SNPs genotyped in the chr 9q33.2 region demonstrated strong statistical evidence for the TRAF1-region harboring RA risk variants (P_(comb)=4.15E-08) and (ii) haplotype analysis of SNPs within the 70 kb LD Block 1, identified a common protective haplotype (P_(comb)=3.08E-08) and a less frequent risk haplotype (P_(comb)=8.00E-09). The three representative SNPs (rs2239657, rs7021049 and rs7021880) were strongly associated with RF-positive disease and trended towards association in RF-negative disease.

Logistic regression was used to tease apart association signals from LD patterns. The pairwise analyses of the combined datasets suggest there may be two independent statistical signals of association to RA at chr 9q33.2—one in the TRAF1 region represented by rs7021049 and one in the GSN region represented by rs 10985196 (Table 13). Analyses of the individual sample sets showed rs10985196 was independently associated with disease risk in Sample Set 2 while rs7021049 shows consistent association across all three sample sets (data not presented).

The original RA-associated, 9q33.2 SNP identified in the genome-wide scan, rs1953126, is located within LD Block 1, 1 kb upstream of the 5′ end of PHF19, the human homologue of the Drosophila polycomblike protein (PCL) gene. In Drosophila, the protein encoded by this gene is part of the 1MDa extra sex combs and enhancer of zeste [ESC-E(Z)] complex which is thought to mediate transcriptional repression by modulating the chromatin environment of many developmental regulatory genes such as homeobox genes. In humans, this gene encodes two nuclear proteins that appear to be upregulated in multiple cancers, and preliminary evidence suggests that deregulation of these genes may play a role in tumor progression [49].

TRAF1 encodes a protein that is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family that associates with, and mediates, signal transduction from various receptors including a subset of the TNFR superfamily. There are six members of this family of adaptor proteins; however, TRAF1 is unique in that while it contains the hallmark carboxyl-terminal TRAF domain, it has a single zinc finger in the amino-terminal part, and the N-terminal RING finger domain (required for NF-κB activation) is missing. TRAF1 appears to have both anti-apoptotic and anti-proliferative effects [50, 51]. In addition, this protein has been found to be elevated in malignancies of the B cell lineage [52-57]. This observation is interesting given that the risk of lymphoma, particularly diffuse large B cell lymphomas, appears to be increased in the subset of RA patients with very severe disease, independent of treatment [58, 59]. It is clear that TRAF1 plays an important role in immune cell homeostasis, making it an excellent candidate gene for RA. Further, in vitro work suggests that TNFα-mediated synovial hyperplasia, a major pathophysiologic feature of RA, may be correlated with upregulation of TRAF molecules, particularly TRAF1 [60]. Given that TNF blockade has proved a highly effective therapy for RA [61, 62], and response to TNF inhibitors among RA patients is known to vary, TRAF1 variants can be useful for assessing (e.g., predicting) an individual's response to TNF inhibitors as well as other drug treatments.

SNPs in LD Block 1 could differentially regulate the expression of the C5 gene. C5 encodes a zymogen that is involved in all three pathways of complement activation. Traditionally, the complement system has been viewed as a central part of the innate immune system in host defenses against invading pathogens and in clearance of potentially damaging cell debris; however complement activation has also recently been implicated in the pathogenesis of many inflammatory and immunological diseases. Proteolytic cleavage of C5 results in C5a (one the most potent inflammatory peptides) and C5b (a component of the membrane attack complex (MAC) that can cause lysis of cells and bacteria). Genetic studies in various mouse models of RA, including collagen-induced arthritis (CIA) and the K/BXN T cell receptor transgenic mouse model of inflammatory arthritis, have provided evidence that C5 (or a variant in strong LD) plays a role in disease [63-65]. Furthermore, anti-C5 monoclonal antibody therapy can prevent and ameliorate disease in both mouse models [66, 67].

Thus, a region on chromosome 9q33.2, particularly variants in TRAF1, is identified herein as being associated with risk for RA. In addition to developing targeted therapies with knowledge of predisposing variants underlying the onset of RA, the identification of RA susceptibility alleles may encourage earlier monitoring and provide an intervention avenue in advance of significant joint erosion. The analysis disclosed herein of the three known genetic risk factors (the chr 9q33.2 variants disclosed herein, as well as HLA-SE and PTPN22) indicates a >45-fold difference in RA risk depending on an individual's genotype at these three loci. These genetic variants are useful for identifying individuals at increased risk for developing RA, particularly within families with a history of RA, and are also useful as drug response markers, particularly for assessing differential response to TNF inhibitors and other drugs.

Materials and Methods

Subjects and Samples

All RA cases included in this study were white and met the 1987 American College of Rheumatology diagnostic criteria for RA [68]; informed written consent was obtained from every subject. Sample Set 1, which consisted of 475 RA cases and 475 individually-matched controls, was collected by Genomics Collaborative, Inc. All case samples were white North Americans of European descent who where rheumatoid factor (RF) positive. Control samples were healthy white individuals with no medical history of RA, also of European descent. A single control was matched to each case on the basis of sex, age (±5 years), and self-reported ethnic background. The 661 cases in Sample Set 2 were acquired from the North American Rheumatoid Arthritis Consortium (NARAC) and consisted of members from 661 white North American multiplex families [33, 69, 70]. Both RF-positive and RF-negative patients were included in this sample set. Controls for Sample Set 2 were selected from 20,000 healthy individuals enrolled in the New York Cancer Project [71], a population-based prospective study of the genetic and environmental factors that cause disease. Two control individuals were matched to a single, randomly chosen affected sibling from each NARAC family on the basis of sex, age (decade of birth), and self-reported ethnic background. Sample Set 3 was composed of 596 white RA patients from the Leiden University Medical Center and 705 white controls from the same geographic region in The Netherlands [72-74]. Both RF-positive and RF-negative patients were included in this sample set. Table 8 displays the clinical characteristics of all three sample sets and a detailed description of samples that overlap with published studies of this region [34, 35].

Controls (which may also be referred to as “healthy” or “normal” individuals), in addition to having no medical history of RA, also were free of psoriasis, systemic lupus erythematosus, ankylosing spondylitis, and Reiter syndrome, had rheumatoid factor levels below 20 IU, and had no history of bone marrow transplants.

Functional Genome-Wide Scan

The functional genome-wide scan included 25,966 gene-centric SNPs curated from dbSNP, the Applera Genome Initiative [44, 75], and the literature. SNPs were included if they appeared in more than one database and had a minor-allele frequency >1%. Approximately 70% of the SNPs were annotated as missense polymorphisms. The majority of the remaining SNPs were either located within putative transcription-factor site motifs or within acceptor/donor splice site regions or were nonsense polymorphisms.

Genotyping

Allele-specific, real-time quantitative PCR [76] was used to amplify 3 ng of pooled DNAs and infer SNP allele frequencies as previously detailed [44]. Individual genotyping on SNPs was performed on 0.3 ng of DNA using a similar protocol. Blinded to case-control status, custom-made in-house software was used to call genotypes, followed by hand-curation. Individual genotyping accuracy has been estimated to be >99.8% by comparison with an independent method. HLA-DRB1 genotyping was performed using sequence-specific oligonucleotide probes as previously described [9]. Shared epitope (SE) status [77] was determined from the probe hybridization patterns. For this study, DRB1 alleles positive for the SE include: 0101, 0102, 0401, 0404, 0405, 0408 and 1001.

Fine-Scale Mapping SNP Selection

To identify SNPs for inclusion in fine-scale mapping of the 9q33.2 region, two different disease models were postulated: 1) a model where the originally identified SNP is in linkage disequilibrium with one or more causative SNPs and 2) a model of allelic heterogeneity where several alleles at the locus independently predispose individuals to RA. To address both of these models, the region to be interrogated was first defined by calculating pairwise linkage disequilibrium (r²) values between the originally identified SNP 5′ of PHF19, rs1953126, and all HapMap-genotyped SNPs within 500 kb flanking either side for the CEPH samples (Utah residents with ancestry from northern and western Europe, or CEU individuals) [36]. With this information, a broad region was defined spanning 668 kb, from MEGF9 (177 kb upstream of rs1953126) to STOM (491 kb downstream of rs1953126), for follow-up genotyping. SNPs within this region were partitioned into those in moderate to high LD (r²>0.20) with rs1953126 to address the first model, and those in low LD (r²<0.20) with rs1953126 to address the second model. The power-based SNP selection program Redigo [78] was then used on the low LD set of SNPs to identify a reduced number of SNPs (tagging SNP set) that retained high power to detect association. Those SNPs in moderate to high LD with the original SNP were reduced by selecting a subset of representative SNPs of any groups exhibiting extremely high inter-group LD (r²>0.98). Further, any putative functional SNPs were automatically included in the fine-scale mapping effort if high-quality genotyping assays could be constructed for them. The resulting set of 137 SNPs was genotyped in Sample Set 1 and the data analyzed. Additional removal of fine-scale mapping SNPs was performed for evaluation in subsequent sample sets on the basis of association results and refined LD patterns: a subset of 72 SNPs were selected for genotyping in Sample Set 2 and 42 SNPs were genotyped in Sample Set 3.

Statistical Analyses

The Cochran-Armitage trend test [79] was used to calculate P-values for individual SNPs. A William's-corrected G-test [37] was used to calculate P-values for genotypic association. P-values were corrected for multiple testing using the method of Dunn-Sidak [37]. Odds ratios and confidence intervals were calculated according to standard procedures. Hardy-Weinberg equilibrium testing was accomplished through the exact test of Weir [80]. P-values were combined across sample sets using the Fisher's combined P-value, or omnibus procedure [81] Likewise, Mantel-Haenszel common odds ratios [82] were calculated to combine data across sample sets. To avoid the small-count limitations of asymptotic-derived confidence intervals, a Monte Carlo simulation was written in XLISP-STAT to calculate 95% confidence intervals on the Mantel-Haenszel common odds ratios. 20,000 iterations of the Monte Carlo were typically performed for these confidence intervals. The standard measure of pairwise linkage disequilibrium (the r² statistic from estimated 2-site haplotypes) was used to characterize the genetic architecture of the region. The program LDMAX with an EM algorithm was used to perform the r² calculation [83].

Genetic Analyses

Haplotype Analysis

Haplotypes were estimated from unphased genotype data and evaluated for association with RA through the Haplo.Stats software package [39]. A sliding window of haplotype association was calculated using a window size of 5 SNPs. Global P-values (calculated across all haplotypes within a window) and haplotype-specific ORs and P-values were calculated. Additional haplotype analyses were performed using a combination of the Pseudo-Gibbs sampling algorithm in the program SNPAnalyzer [40] and the Haplo.Stats package.

Genetic Background-Conditioned Analysis

A panel of 749 SNPs previously selected to be informative for classifying individuals of European descent into Northern and Southern geographical groups was applied to case and control samples from the second sample set as described previously [41]. Applying this method, 367 cases and 525 controls from Sample Set 2 were placed into a northern European ancestry cluster. Each case or control individual had a greater than 0.95 probability of belonging to the northern European cluster. The remaining cases and controls from this study were binned into an “Other” category. A Breslow-Day analysis [84] was applied to the stratified data to test for heterogeneity in ORs between the two groups for the 9q33.2-linked SNPs studied here. To test for association conditioned on these stratified data, a Mantel-Haenszel P-value was also calculated.

Subphenotype Analysis: Rheumatoid Factor

Rheumatoid Factor (RF) levels were measured in cases as previously described [85, 86]. To test for heterogeneity of effect between RF-positive and RF-negative patients, two different methods were used. In sample set 2, where case-control matching was part of the study design, the Breslow-Day [84] test was used. Since individual matching was not incorporated into Sample Set 3, a Monte Carlo simulation was used to compare the effect size for RF-positive patients versus all controls to the effect size for RF-negative patients versus all controls. Similar to other tests of homogeneity of odds ratios, a test statistic was constructed measuring the departure between normalized odds ratios comparing two groups (see equation S1 in the “Supporting Information” section of Example 1 below) and a Monte Carlo simulation was run to account for correlated odds ratios in the null distribution. Monte Carlo P-values were calculated in the traditional manner.

Logistic Regression

Logistic regression models were performed to assess the relative importance of 27 SNPs chosen as distinct representatives of groups of SNPs with pairwise r² values >0.90. First, a logistic regression model for each unique pair of SNPs was performed. These pairwise models assumed a multiplicative effect on the risk of RA for each additional copy of an allele. The p-values and odds ratios for the effect of each SNP when controlling for each alternative SNP were examined visually to determine if any SNP showed obvious patterns (attenuating the risk of each alternate SNP and retaining risk when adjusted for each alternate SNP). These types of patterns might be expected under a disease model of a single functional SNP. For models in which both SNPs remained strongly associated (p<0.01), additional models were performed to determine if adding a third SNP significantly improved the model. To examine multi-SNP relationships in a more automated fashion, both a forward as well as a backward stepwise logistic regression procedure was performed on each sample set individually as well as on the combined sample sets. The stepwise models were performed coding the genotypes with indicator variables and with a significance level of 0.05 for the 2 degree of freedom score test (for entry) or Wald test (for exit) on the effect of the SNP used as a threshold for entry or exit from the model. Models applied to the combined sample sets also forced sample set as a covariate in the model. The final model from each procedure was also applied to the other sample sets to assess consistency of the models across sample sets. The p-value from the likelihood ratio test of the global null hypothesis for each model is reported. All logistic regression models were performed using SAS version 9.

Multi-Locus RA Risk Calculations

Risk for RA given every possible 3-locus genotype combination at the HLA-DRB1 shared epitope, the R620 W SNP in PTPN22, and 3-SNP TRAF1 diplotypes was calculated for sample set 1 using Bayes' theorem (see equations S2 and S3 in the “Supporting Information” section of Example 1 below) assuming conditional independence between loci (the commonly-used Naive Bayes model for predictive modeling) and a range of RA prevalence values (1%, 10% and 30%). Theoretical calculations (not shown) demonstrate that unless both sample sizes and epistatic effects are very large, probability estimates of the jointly-occurring genotypes have lower error rates assuming conditional independence between loci. Therefore, fully-factorizing the probability of multi-locus genotypes (using the conditional independence assumption) is warranted under a broad range of the parameter space. By estimating the posterior probability of RA for every possible multi-locus genotype combination, accurate individual-based prognosis is possible. Confidence intervals on the relative risk estimates were obtained through simulation. Due to the selection of loci for inclusion in the model, some overfitting may be present.

Supporting Information

Rheumatoid Factor Analysis

Investigating the effect heterogeneity between two case groups, RF-positive and RF-negative disease, with the same group of controls, a Monte Carlo procedure was devised using a simple test statistic to measure the normalized departure between two odds ratios. As the correlated nature of the two odds ratios were automatically incorporated into the Monte Carlo simulation, the appropriate null distribution of this test statistic was obtained without complicated analytic techniques. The test statistic constructed was

$\begin{matrix} {{T = \left( {\frac{\ln \; {OR}_{1}}{\sqrt{\frac{1}{x_{1}} + \frac{1}{x_{2}} + \frac{1}{z_{1}} + \frac{1}{z_{2}}}} - \frac{\ln \; {OR}_{2}}{\sqrt{\frac{1}{y_{1}} + \frac{1}{y_{2}} + \frac{1}{z_{1}} + \frac{1}{z_{2}}}}} \right)^{2}};} & \left( {{eqn}\mspace{14mu} {S1}} \right) \end{matrix}$

where OR₁ is the allelic odds ratio comparing RF-positive cases to the control group; OR₂ is the allelic odds ratio comparing RF-negative cases to the control group; and x₁ and x₂ are the allelic counts for the A₁ allele and A₂ allele in the RF-positive case group, respectively. Using similar notation, y₁ and y₂ are the allelic counts in RF-negative cases, and z₁ and z₂ are the allelic counts in the control group.

Multilocus RA Risk Calculations

The probability of RA given the genotypes at the three predisposing loci is

$\begin{matrix} {{P\left( {\left. {RA} \middle| G_{HLA} \right.,G_{{PTPN}\; 22},G_{{TRAF}\; 1}} \right)} = \frac{{P\left( {G_{HLA},G_{{PTPN}\; 22},\left. G_{{TRAF}\; 1} \middle| {RA} \right.} \right)}{P({RA})}}{P\left( {G_{HLA},G_{{PTPN}\; 22},G_{{TRAF}\; 1}} \right)}} & \left( {{eqn}\mspace{14mu} {S2}} \right) \end{matrix}$

Assuming conditional independence, one can fully factorize

$\begin{matrix} {\approx \frac{{P({RA})}{\prod{P\left( G \middle| {RA} \right)}}}{{{P({RA})}{\prod{P\left( G \middle| {RA} \right)}}} + {\left\lbrack {1 - {P({RA})}} \right\rbrack {\prod{P\left( G \middle| {CT} \right)}}}}} & \left( {{eqn}\mspace{14mu} {S3}} \right) \end{matrix}$

where P(RA) is the probability of RA, and where P(G|RA) and P(G|CT) are the probabilities of a genotype in RA patients and controls, respectively.

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Example 2 Linkage Disequilibrium (LD) SNPs Associated with Autoimmune Disease, Particularly Rheumatoid Arthritis

Another investigation was conducted to identify additional SNPs that are calculated to be in linkage disequilibrium (LD) with certain “interrogated SNPs” that have been found to be associated with autoimmune disease, particularly RA, as described herein and shown in the tables. The interrogated SNPs are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 4. The methodology is described earlier in the instant application. To summarize briefly, the power threshold (7) was set at an appropriate level, such as 51%, for detecting disease association using LD markers. This power threshold is based on equation (31) above, which incorporates allele frequency data from previous disease association studies, the predicted error rate for not detecting truly disease-associated markers, and a significance level of 0.05. Using this power calculation and the sample size, a threshold level of LD, or r² value, was derived for each interrogated SNP (r_(T) ², equations (32) and (33) above). The threshold r_(T) ² value is the minimum value of linkage disequilibrium between the interrogated SNP and its LD SNPs possible such that the non-interrogated SNP still retains a power greater or equal to T for detecting disease association.

Based on the above methodology, LD SNPs were found for the interrogated SNPs. Several exemplary LD SNPs for the interrogated SNPs are listed in Table 4; each LD SNP is associated with its respective interrogated SNP. Also shown are the public SNP IDs (rs numbers) for the interrogated and LD SNPs, when available, and the threshold r² value and the power used to determine this, and the r² value of linkage disequilibrium between the interrogated SNP and its corresponding LD SNP. As an example in Table 4, the interrogated SNP rs10435844 (hCV11266229) was calculated to be in LD with rs10760121 (hCV11266268) at an r² value of 0.9666, based on a 51% power calculation, thus establishing the latter SNP as a marker associated with autoimmune disease as well.

In general, the threshold r_(T) ² value can be set such that one with ordinary skill in the art would consider that any two SNPs having an r² value greater than or equal to the threshold r_(T) ² value would be in sufficient LD with each other such that either SNP is useful for the same utilities, such as determining an individual's risk for autoimmune disease such as RA, for example. For example, in various embodiments, the threshold r_(T) ² value used to classify SNPs as being in sufficient LD with an interrogated SNP (such that these LD SNPs can be used for the same utilities as the interrogated SNP, for example) can be set at, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99, 1, etc. (or any other r² value in-between these values). Threshold r_(T) ² values may be utilized with or without considering power or other calculations.

All publications and patents cited in this specification are herein incorporated by reference in their entirety. Modifications and variations of the described compositions, methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments and certain working examples, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention that are obvious to those skilled in the field of molecular biology, genetics and related fields are intended to be within the scope of the following claims.

TABLE 3  Marker Alleles Primer 1 (Allele-specific Primer) Primer 2 (Allele-specific Primer) Common Primer hCV11266229 G/T GCGGAGACTTCATCCTGATG (SEQ ID NO: 585) GCGGAGACTTCATCCTGATT (SEQ ID NO: 586) CCGCTTTGGTCTGGATGTGA (SEQ ID NO: 587) hCV11720383 A/G TTCCTGACATGCCCCA (SEQ ID NO: 588) TCCTGACATGCCCCG (SEQ ID NO: 589) TGTCCCCCTGCCTTGACTTAT (SEQ ID NO: 590) hCV11720386 A/G GCTTCCCAAAAGACTAATGCTA (SEQ ID NO: 591) GCTTCCCAAAAGACTAATGCTG (SEQ ID NO: 592) GGATAATTTTGCCAGATCGCCTTCTA (SEQ ID NO: 593) hCV11720394 A/T CCTCGGTCATCAATGCTTATAATTA (SEQ ID NO: 594) CCTCGGTCATCAATGCTTATAATTT CAGCACGAATTATTCCAGCTTTCTTTG (SEQ ID NO: 596) (SEQ ID NO: 595) hCV11720402 C/T TGGGAAATTCAAGGCG (SEQ ID NO: 597) CTGGGAAATTCAAGGCA (SEQ ID NO: 598) TTTAAGTCCTGGGTAAACTAAATAGA (SEQ ID NO: 599) hCV11720413 C/T GAAAACAGCTTTACAGACAAGC (SEQ ID NO: 600) AGAAAACAGCTTTACAGACAAGT (SEQ ID NO: 601) GGAAGCCACAGAAAGGCATCAG (SEQ ID NO: 602) hCV11720414 A/G GCCCAATGAATAATAATCACAAAAGTT GCCCAATGAATAATAATCACAAAAGTC AGCAATGCTGTGGAAGGAGAGATAT (SEQ ID NO: 605) (SEQ ID NO: 603) (SEQ ID NO: 604) hCV11720421 A/G AGAGAAGGTGTGTCCAACA (SEQ ID NO: 606) GAGAAGGTGTGTCCAACG (SEQ ID NO: 607) AGAGGTGAGCACTTCGCTCTATC (SEQ ID NO: 608) hCV11840638 A/G ACTCCGCAGGCATCAT (SEQ ID NO: 609) ACTCCGCAGGCATCAC (SEQ ID NO: 610) GGAAGCAAAGTGGAGTGTGAACAATA (SEQ ID NO: 611) hCV1219005 A/G CAAACCTGATCACTTTAGGGAA (SEQ ID NO: 612) CAAACCTGATCACTTTAGGGAG (SEQ ID NO: 613) GGAGAATGCGGCTCACACTC (SEQ ID NO: 614) hCV1219006 C/G GGGAAGTCTTTCTGGATTGTTG (SEQ ID NO: 615) GGGAAGTCTTTCTGGATTGTTC (SEQ ID NO: 616) CCATAGCTGCTCTGAAGGGACTG (SEQ ID NO: 617) hCV1434291 A/G CTTTCTGTCTTGCCCCAT (SEQ ID NO: 618) CTTTCTGTCTTGCCCCAC (SEQ ID NO: 619) AGGATGGGCTAAGGAATTACTGAAATACC (SEQ ID NO: 620) hCV1434292 A/C GCAGAGGAAATCCAGTTATCTT (SEQ ID NO: 621) GCAGAGGAAATCCAGTTATCTG (SEQ ID NO: 622) CCGTTCCCCATCAGCTGATTTAC (SEQ ID NO: 623) hCV1452636 A/G GCCACACAATCTAGCAATTCT (SEQ ID NO: 624) GCCACACAATCTAGCAATTCC (SEQ ID NO: 625) TCATGCACTGGTGGACACTTAGAT (SEQ ID NO: 626) hCV1452662 A/C CCAAGGAGTCTACACTCTCAA (SEQ ID NO: 627) CCAAGGAGTCTACACTCTCAC (SEQ ID NO: 628) GAGGTGGCATGCAAACACA (SEQ ID NO: 629) hCV15751719 A/G GGTTCTTTACTTGCTTCAGTTATTAT (SEQ ID NO: 630) GGTTCTTTACTTGCTTCAGTTATTAC ATGTCCAGGGGATTCAAGAATGAGTA (SEQ ID NO: 632) (SEQ ID NO: 631) hCV15757738 A/T CCACCACTGGCCTATGAT (SEQ ID NO: 633) CCACCACTGGCCTATGAA (SEQ ID NO: 634) GTAATGCTGCTTTACCTCAGCTAGAAC (SEQ ID NO: 635) hCV15849105 A/G GCCAGTCTTGGATTCATCTTATATACTA CCAGTCTTGGATTCATCTTATATACTG AGCGAGGCTCCGTCTCAA (SEQ ID NO: 638) (SEQ ID NO: 636) (SEQ ID NO: 637) hCV15849116 C/T TCAGCCTTAGAACAATGCTATG (SEQ ID NO: 639) GTCAGCCTTAGAACAATGCTATA (SEQ ID NO: 640) GCTCTGCTCCCAAGATTTTCTGTT (SEQ ID NO: 641) hCV15870898 C/T GGAGCTCCCCATTTTGG (SEQ ID NO: 642) AGGAGCTCCCCATTTTGA (SEQ ID NO: 643) CCACTAGCCAGGCAGGATAAGAT (SEQ ID NO: 644) hCV15875924 A/T ACTGCTCAGTGTCTTTCCAA (SEQ ID NO: 645) ACTGCTCAGTGTCTTTCCAT (SEQ ID NO: 646) CCTGGGGAGCTCTGAGTGAT (SEQ ID NO: 647) hCV15875965 A/T CTTTTGCAAGTGAGGCATAGA (SEQ ID NO: 648) TTTTGCAAGTGAGGCATAGT (SEQ ID NO: 649) GCTGCTCCGTGGAGTAACTC (SEQ ID NO: 650) hCV15974495 C/T ACAGAATGATGTAGCTGTCG (SEQ ID NO: 651) TACAGAATGATGTAGCTGTCA (SEQ ID NO: 652) TCCTGCAGATCTGGAGAATC (SEQ ID NO: 653) hCV16077967 C/T AACACATTTGAGTGGGTACAC (SEQ ID NO: 654) AAACACATTTGAGTGGGTACAT (SEQ ID NO: 655) CTGACACACCATCCTCATTGGTTTAG (SEQ ID NO: 656) hCV16175379 A/G CCATACCTTGTTCCGGAAA (SEQ ID NO: 657) CCATACCTTGTTCCGGAAG (SEQ ID NO: 658) AATGGAGATGGCACTGGAAAGAGA (SEQ ID NO: 659) hCV16234785 C/T TGCCTCAAGTGCTTTACG (SEQ ID NO: 660) GTGCCTCAAGTGCTTTACA (SEQ ID NO: 661) AACGTCAGCCTCAGTGACTACTTT (SEQ ID NO: 662) hCV16234795 C/G CTTGGGAAAGTCATTAGTACAAAC (SEQ ID NO: 663) CTTGGGAAAGTCATTAGTACAAAG (SEQ ID NO: 664) TCCTTCAAGGTAAGCATCTGAGTGT (SEQ ID NO: 665) hCV1632189 G/T GGGAAATCTTGTTGGATAGTCTG (SEQ ID NO: 666) GGGAAATCTTGTTGGATAGTCTT (SEQ ID NO: 667) GCAGCTCTCCTTGACTAGGAGTAAT (SEQ ID NO: 668) hCV1632190 C/T TTCTGATGACTGATCAAACAGAC (SEQ ID NO: 669) TTCTGATGACTGATCAAACAGAT (SEQ ID NO: 670) GCTGAGATTCAGTACTTCAAGTTTAACACAT (SEQ ID NO: 671) hCV1761888 C/T TGCCCTTTATTTACATGACG (SEQ ID NO: 672) GTGCCCTTTATTTACATGACA (SEQ ID NO: 673) AAAAGGCAATTCACAAAAGAG (SEQ ID NO: 674) hCV1761894 A/G CCTATGGAGATATGAACTGGTAAAAT (SEQ ID NO: 675) CCTATGGAGATATGAACTGGTAAAAC ACGAGTGGAGTCATTGAATTGTAGCTA (SEQ ID NO: 677) (SEQ ID NO: 676) hCV1917481 C/T TCTCAGTGCAAACTGTTCAAC (SEQ ID NO: 678) TCTCAGTGCAAACTGTTCAAT (SEQ ID NO: 679) CCTTCAGTGCTTCCTCAAAGCTTAAT (SEQ ID NO: 680) hCV22272061 C/G GCTAATTGAAAGCTAATGATTCCTTG (SEQ ID NO: 681) GCTAATTGAAAGCTAATGATTCCTTC ATGGTGTTTCCCTGCCTCTGTA (SEQ ID NO: 683) (SEQ ID NO: 682) hCV22272588 G/T TTGAACCCCTGTCAAAGATG (SEQ ID NO: 684) CATATTGAACCCCTGTCAAAGATT (SEQ ID NO: 685) CCCACTATGATTGGTGTAGCTGTAGA (SEQ ID NO: 686) hCV25473087 C/T GACCAGTTGGTAGGAGGG (SEQ ID NO: 687) TGACCAGTTGGTAGGAGGA (SEQ ID NO: 688) CGTCACTCCAGATGGGAGATTAAG (SEQ ID NO: 689) hCV25612709 A/G CAGGTAAGAGATGTTGAAACTGT (SEQ ID NO: 690) AGGTAAGAGATGTTGAAACTGC (SEQ ID NO: 691) GGGGAACCACTCAGGATTAGAGA (SEQ ID NO: 692) hCV25751916 A/C ACAACCAGATTTGATCATCATCAA (SEQ ID NO: 693) CAACCAGATTTGATCATCATCAC (SEQ ID NO: 694) TCTCCTCTGCTGCCTTCATTTCT (SEQ ID NO: 695) hCV25763321 A/G CTCCTCCTGGCTCTCA (SEQ ID NO: 696) TCCTCCTGGCTCTCG (SEQ ID NO: 697) CTGGAGCAGAACCTGTCAGAC (SEQ ID NO: 698) hCV25766419 G/T GGTTCTAACCCCATCTTTCC (SEQ ID NO: 699) GGTTCTAACCCCATCTTTCA (SEQ ID NO: 700) CTTGGCAGTGTAGAAGGCTGAAAC (SEQ ID NO: 701) hCV26144018 A/G TCCTCCACTACCCTCAGA (SEQ ID NO: 702) CCTCCACTACCCTCAGG (SEQ ID NO: 703) GTCTCCACCTTCACGATGTTTACAT (SEQ ID NO: 704) hCV26144282 A/T TCAGGACAAGAATCTCATTTCATT (SEQ ID NO: 705) TTCAGGACAAGAATCTCATTTCATA TATGAGCCTTTCACATACGTGTATTACAGA (SEQ ID NO: 706) (SEQ ID NO: 707) hCV26144366 G/T GCAAAGAGCTGAGAGAATCC (SEQ ID NO: 708) GCAAAGAGCTGAGAGAATCA (SEQ ID NO: 709) GACAGACACAAGGACCATCCTGATA (SEQ ID NO: 710) hCV2644 A/C CTGCAGGTATTTGGGGAA (SEQ ID NO: 711) CTGCAGGTATTTGGGGAC (SEQ ID NO: 712) GTATGGGAAGAGCTTCACCTACTGT (SEQ ID NO: 713) hCV27476319 A/G CCAAACTTACCTGGCTGTTTATA (SEQ ID NO: 714) CAAACTTACCTGGCTGTTTATG (SEQ ID NO: 715) GTGTTTTGCCTGGGTTTTGAAGAAC (SEQ ID NO: 716) hCV2783582 A/G CTCATAAGAAGGTCACATGTCAT (SEQ ID NO: 717) CTCATAAGAAGGTCACATGTCAC (SEQ ID NO: 718) ATGTATGCCATGCCACTTTTGTCA (SEQ ID NO: 719) hCV2783586 C/G TGTTCATTCTGTGTACCTTCAG (SEQ ID NO: 720) TGTTCATTCTGTGTACCTTCAC (SEQ ID NO: 721) GGCTATTTCCTGCCATCTCTGTAAAC (SEQ ID NO: 722) hCV2783589 C/T GCTTTCAGATAACAGACAAACAC (SEQ ID NO: 723) AGCTTTCAGATAACAGACAAACAT (SEQ ID NO: 724) CTGATGAGCGGCTTCGGTTAAA (SEQ ID NO: 725) hCV2783590 C/T CAATGGGGACAATCTCAGC (SEQ ID NO: 726) ACAATGGGGACAATCTCAGT (SEQ ID NO: 727) ATTCATAGATGAGGGTATTTCTGGTGTTGA (SEQ ID NO: 728) hCV2783591 C/G CCCTGCTGACACCTTAATC (SEQ ID NO: 729) CCCTGCTGACACCTTAATG (SEQ ID NO: 730) CGGGATTAAGGGGACAGTTCTATC (SEQ ID NO: 731) hCV2783597 G/T CCACCTCCTAGCTTGTAGAG (SEQ ID NO: 732) CCACCTCCTAGCTTGTAGAT (SEQ ID NO: 733) GGGTCTCAGGAGAACTCGATTGT (SEQ ID NO: 734) hCV2783604 C/T ACTTAACATCCTGTTATCACATTCTG CACTTAACATCCTGTTATCACATTCTA GCACCCGGCCTTGACTT (SEQ ID NO: 737) (SEQ ID NO: 735) (SEQ ID NO: 736) hCV2783608 A/T GTAGTAGGGTCCTGACTTGA (SEQ ID NO: 738) GTAGTAGGGTCCTGACTTGT (SEQ ID NO: 739) GAGAGAAGCCTGGGCAATACTG (SEQ ID NO: 740) hCV2783611 A/G GGGGAACCTCCGTCTGT (SEQ ID NO: 741) GGGAACCTCCGTCTGC (SEQ ID NO: 742) AAAGTTTTGCTTCATCAACTACA (SEQ ID NO: 743) hCV2783618 C/T GCCAGCTGACAAACACTG (SEQ ID NO: 744) GGCCAGCTGACAAACACTA (SEQ ID NO: 745) CCAAGGTCAGCGGCTCAAA (SEQ ID NO: 746) hCV2783620 C/G TGCCCCAGATGTGTTTTC (SEQ ID NO: 747) TGCCCCAGATGTGTTTTG (SEQ ID NO: 748) TGAGCTGGATTCCTGGTGGATAAG (SEQ ID NO: 749) hCV2783621 C/T TGAGTGTGAGAAAGGAGATCTG (SEQ ID NO: 750) CTGAGTGTGAGAAAGGAGATCTA (SEQ ID NO: 751) GCTCTGATGCTTGGGAAAGTCAT (SEQ ID NO: 752) hCV2783625 A/G GGAGGTGACCTTGGATTATCT (SEQ ID NO: 753) GGAGGTGACCTTGGATTATCC (SEQ ID NO: 754) TTGTGGTCCCTTCCTCCATCTTC (SEQ ID NO: 755) hCV2783633 G/T GTTCCAAGAACATGCATTTGG (SEQ ID NO: 756) AGTTCCAAGAACATGCATTTGT (SEQ ID NO: 757) CTCTGAGCTGGTCCCTCTCAT (SEQ ID NO: 758) hCV2783634 C/G GAGACCATTATCAGCTCACG (SEQ ID NO: 759) GAGACCATTATCAGCTCACC (SEQ ID NO: 760) GAGGGCCAGGGTTCTAAATTGTA (SEQ ID NO: 761) hCV2783638 C/T ACTTTCACAGTGGTTTCAGATC (SEQ ID NO: 762) ACTTTCACAGTGGTTTCAGATT (SEQ ID NO: 763) CCCAGGGCCCACAGTTAGTAA (SEQ ID NO: 764) hCV2783641 C/G CTTTTCTTATTAGAGCAGGTTGG (SEQ ID NO: 765) CTTTTCTTATTAGAGCAGGTTGC (SEQ ID NO: 766) TCCTTCCCCTGGTTTGGGATAAA (SEQ ID NO: 767) hCV2783653 A/G CAACCTGTGAACATGAGAATACT (SEQ ID NO: 768) AACCTGTGAACATGAGAATACC (SEQ ID NO: 769) GGTGTTGTTTGCCTCTATCACATCT (SEQ ID NO: 770) hCV2783655 A/G TCCAAGCCTCACTTTGTGT (SEQ ID NO: 771) CCAAGCCTCACTTTGTGC (SEQ ID NO: 772) CTGCTGTATGAACTTGGGTCTGG (SEQ ID NO: 773) hCV2783663 G/T CTTCATCTTGGAATGCTCAAAAG (SEQ ID NO: 774) CTTCATCTTGGAATGCTCAAAAT (SEQ ID NO: 775) ACCATTAGACTAGTTAAGATCACTAAGGATGTGA (SEQ ID NO: 776) hCV2783668 C/T GGCTACTTGTGAGTTCTTTGG (SEQ ID NO: 777) GGCTACTTGTGAGTTCTTTGA (SEQ ID NO: 778) GGTATTTGGCAACTGTTAACTTTGTGGA (SEQ ID NO: 779) hCV2783677 C/T GGAACAGATGATTTCAATGGTCTC (SEQ ID NO: 780) GGAACAGATGATTTCAATGGTCTT (SEQ ID NO: 781) GTTTCTTACAAGCATAAAGGTGCCTTACA (SEQ ID NO: 782) hCV2783678 C/G CCAGTAGAGGTAAATGAAGAACTTTG (SEQ ID NO: 783) CCAGTAGAGGTAAATGAAGAACTTTC CTGTTTAGGACATAGCTGACACTCAA (SEQ ID NO: 785) (SEQ ID NO: 784) hCV2783699 C/T CATGTGCAGGTCTGTTGTAC (SEQ ID NO: 786) CATGTGCAGGTCTGTTGTAT (SEQ ID NO: 787) GTGGAGGGTGAGAGAAGGGTAAAG (SEQ ID NO: 788) hCV27912350  A/G GCAAATGTAGGACTCTTGATGTTA (SEQ ID NO: 789) CAAATGTAGGACTCTTGATGTTG (SEQ ID NO: 790) CGAACAGAGCCTAGCAAATGGTAAAT (SEQ ID NO: 791) hCV27912351  G/T GCCTGGGGCTTATAAAAGG (SEQ ID NO: 792) GCCTGGGGCTTATAAAAGT (SEQ ID NO: 793) GGCAAACAACAGGCAAATGTGA (SEQ ID NO: 794) hCV28010798  C/G TGAGGAGACAAAGTGGCTC (SEQ ID NO: 795) TGAGGAGACAAAGTGGCTG (SEQ ID NO: 796) AGTGATAGGGAATTTGTAGCCGTCTTT (SEQ ID NO: 797) hCV29005933  C/T TTGCTTTAACTCCCTTGTAGC (SEQ ID NO: 798) CTTGCTTTAACTCCCTTGTAGT (SEQ ID NO: 799) CAGGCTCGGATGAACCTCAAAG (SEQ ID NO: 800) hCV29005936  A/G TGGGTTGAAGCCTCAATTCTA (SEQ ID NO: 801) GGGTTGAAGCCTCAATTCTG (SEQ ID NO: 802) CGCAATTATTTGGACAAATGAGGAAACATG (SEQ ID NO: 803) hCV29005938  C/G TCCTTAGCCCTTTAATTGGATTTG (SEQ ID NO: 804) TCCTTAGCCCTTTAATTGGATTTC (SEQ ID NO: 805) TTGCAGAGGAATCGGAATCAGGATATT (SEQ ID NO: 806) hCV29005968  C/T TCCATACCTCTGTTCGGC (SEQ ID NO: 807) TTCCATACCTCTGTTCGGT (SEQ ID NO: 808) TCAGGGCTACGGTGATGTTTCA (SEQ ID NO: 809) hCV29005978  A/G AGCTATCCCCCTACCGT (SEQ ID NO: 810) GCTATCCCCCTACCGC (SEQ ID NO: 811) GACAGGAAATTCCCCTGAACTCT (SEQ ID NO: 812) hCV29005979  A/T TGGTCCTACTGTCCCTACT (SEQ ID NO: 813) TGGTCCTACTGTCCCTACA (SEQ ID NO: 814) GCCCTGTTCCTTCCTGTGTT (SEQ ID NO: 815) hCV29006006  A/T GAGTCAGTCTTTTATGATCACACT (SEQ ID NO: 816) GAGTCAGTCTTTTATGATCACACA (SEQ ID NO: 817) GCTGCATTGACTATTTGCGAGATATTTTG (SEQ ID NO: 818) hCV29752541  A/T CTGCACAAAGGAGAACACA (SEQ ID NO: 819) CTGCACAAAGGAGAACACT (SEQ ID NO: 820) CGTACTCCAATCTGGGACTAGA (SEQ ID NO: 821) hCV29824827  C/T TTGAGCTTTGGGCAAGTC (SEQ ID NO: 822) TTTGAGCTTTGGGCAAGTT (SEQ ID NO: 823) TGTGACTCCTCACAACAACTTATCATGT (SEQ ID NO: 824) hCV30167357  C/G CTCCTATCCAAGTGTTAACCAG (SEQ ID NO: 825) TCCTATCCAAGTGTTAACCAC (SEQ ID NO: 826) TTAGGAGGCTAGCGTAGCAATCTAG (SEQ ID NO: 827) hCV30203282  C/T AGCTTAGGAAACACCAAATTAAAC (SEQ ID NO: 828) ATAAGCTTAGGAAACACCAAATTAAAT TTGATGTGTCATAATGTGCGTTAGCAT (SEQ ID NO: 830) (SEQ ID NO: 829) hCV30293181  A/G GTGGAGCTCACAAAAGAGTTAT (SEQ ID NO: 831) TGGAGCTCACAAAAGAGTTAC (SEQ ID NO: 832) TCTCTGTTCTCAACGGCTCAGTT (SEQ ID NO: 833) hCV3045792 A/G TTGATCACTAACCTTACTCAGTAAAT (SEQ ID NO: 834)  TGATCACTAACCTTACTCAGTAAAC (SEQ ID NO: 835) AGCCCTCAGTAAATGTTAGCCACTAG (SEQ ID NO: 836) hCV3045796 A/T GCCTCTTCATTAAAATCATCACATCAT GCCTCTTCATTAAAATCATCACATCAA GTGACATTGTGTTTTCCTTGATTTAGAAGC (SEQ ID NO: 839) (SEQ ID NO: 837) (SEQ ID NO: 838) hCV3045797 C/G ACTACTGTGGCTGTCTGATC (SEQ ID NO: 840) ACTACTGTGGCTGTCTGATG (SEQ ID NO: 841) GCTACAGGAGGGGAGACTGATTAC (SEQ ID NO: 842) hCV3045798 G/T CTTTATAGGATGCAAATGCTAATGAG (SEQ ID NO: 843) CTTTATAGGATGCAAATGCTAATGAT GGCATCAGAAAGAACAAAGGCTAATT (SEQ ID NO: 845) (SEQ ID NO: 844) hCV3045800 A/T GGGACTTCATTGATGGAAATGTA (SEQ ID NO: 846) GGGACTTCATTGATGGAAATGTT (SEQ ID NO: 847) TGAGCGACGTTTCAGAAGAGTCTT (SEQ ID NO: 848) hCV3045802 C/T GGAGCTGTGACAATCGAG (SEQ ID NO: 849) GGAGCTGTGACAATCGAA (SEQ ID NO: 850) ACTGTATGACTCCCTTTATGTACTACAATACATG (SEQ ID NO: 851) hCV3045803 A/C GCATGGACATGAGACAGATT (SEQ ID NO: 852) GCATGGACATGAGACAGATG (SEQ ID NO: 853) TGCTTGAATCCCCTCCTCACAT (SEQ ID NO: 854) hCV3045812 C/T GCAGTCAGTGCCTATGC (SEQ ID NO: 855) GGCAGTCAGTGCCTATGT (SEQ ID NO: 856) TCCCTCCACCAAATACAGTACTATATTCTACA (SEQ ID NO: 857) hCV30527383  A/G AGAGCCTGGTAAAGAAGGT (SEQ ID NO: 858) GAGCCTGGTAAAGAAGGC (SEQ ID NO: 859) GGCATCTGCTGGCTGAGT (SEQ ID NO: 860) hCV30563728  C/T TGTAATAGTGCATGAAGGACG (SEQ ID NO: 861) AATGTAATAGTGCATGAAGGACA (SEQ ID NO: 862) GCAAACCAACATGGCACATGTATAC (SEQ ID NO: 863) hCV30563729  A/T CGGTGAGAATGCCATGGA (SEQ ID NO: 864) CGGTGAGAATGCCATGGT (SEQ ID NO: 865) AGCCAAATTTACCAGAACAGCTAAACTG (SEQ ID NO: 866) hCV30829490  C/T TGATTCTCCAATGGTTAAGAGC (SEQ ID NO: 867) GTGATTCTCCAATGGTTAAGAGT (SEQ ID NO: 868) TGTTGGCCAGGCTGGTTTCA (SEQ ID NO: 869) hCV30829528  G/T GTAAACCCTACCTAAAATGTACTGG (SEQ ID NO: 870) GTAAACCCTACCTAAAATGTACTGT GAGGAGATGGAGGGGATGATGAC (SEQ ID NO: 872) (SEQ ID NO: 871) hCV30830255  C/T TCCTCCTTGTAGTTAACAATGC (SEQ ID NO: 873) GATATCCTCCTTGTAGTTAACAATGT CAGTCTTACATGCTTCCAAGAAACTGG (SEQ ID NO: 875) (SEQ ID NO: 874) hCV30830340  C/T AGTGGATACTACTGATTTTAGACAAC (SEQ ID NO: 876) GAAGTGGATACTACTGATTTTAGACAAT GGTGTTACTTTGGATCCTAGGGGTATTT (SEQ ID NO: 878) (SEQ ID NO: 877) hCV30830341  A/G GAAATTCACTTCAGTAAACATGTACT (SEQ ID NO: 879) GAAATTCACTTCAGTAAACATGTACC GGAGGTGATGGAGCCAAGATTC (SEQ ID NO: 881) (SEQ ID NO: 880) hCV30830377  A/G TACCCCATTTTCCATGATATGATTA (SEQ ID NO: 882) CCCCATTTTCCATGATATGATTG (SEQ ID NO: 883) TTTATGTGGGTAAATAGTATTTACGGGGTACAC (SEQ ID NO: 884) hCV30830395  C/T TGACCCAGAGTAGAAGCTG (SEQ ID NO: 885) GTTATGACCCAGAGTAGAAGCTA (SEQ ID NO: 886) GCCAGCAAGCAAGTAAAGAAATGATT (SEQ ID NO: 887) hCV30830407  C/G TGTACACATAACAACTGAGAACTG (SEQ ID NO: 888) TGTACACATAACAACTGAGAACTC (SEQ ID NO: 889) CAATAAGCCAATGATGCTGGTACTATCA (SEQ ID NO: 890) hCV30830414  C/T CCTGTGTTATGTTCCACCG (SEQ ID NO: 891) TCCTGTGTTATGTTCCACCA (SEQ ID NO: 892) GCTGCACAGCAGGAAAGAGAAT (SEQ ID NO: 893) hCV30830415  C/T GGACAGAATTCTGCAGGC (SEQ ID NO: 894) AGGACAGAATTCTGCAGGT (SEQ ID NO: 895) CTCAGGACCTCAGACCACTTTAGTTA (SEQ ID NO: 896) hCV30830417  C/T GCACTAGACCTTGCCCG (SEQ ID NO: 897) GCACTAGACCTTGCCCA (SEQ ID NO: 898) ACTGTTCCCAAGACCATGATCACT (SEQ ID NO: 899) hCV30830435  A/T ATCATGATCCGGTCTCTCAT (SEQ ID NO: 900) TCATGATCCGGTCTCTCAA (SEQ ID NO: 901) GGAATGGGGCATTTGGCTATATTGT (SEQ ID NO: 902) hCV30830484  A/G CATGTCTCATTTACCTCCTTTCT (SEQ ID NO: 903) CATGTCTCATTTACCTCCTTTCC (SEQ ID NO: 904) CCCCTTCCAGTTCTGTGATCTATGA (SEQ ID NO: 905) hCV30830503  G/T CAACCTCACAGATTTGGAGAC (SEQ ID NO: 906) CAACCTCACAGATTTGGAGAA (SEQ ID NO: 907) GTTCTCACAGTAATCTGCTGAACAAACT (SEQ ID NO: 908) hCV30830506  A/G AAGGGTCATATTGTCTATTTGAGAT (SEQ ID NO: 909) AAGGGTCATATTGTCTATTTGAGAC (SEQ ID NO: 910) CCAGCACTTCCACTGGTTGTT (SEQ ID NO: 911) hCV30830512  A/G AGGGGACTTATATGACTTGCAT (SEQ ID NO: 912) GGGGACTTATATGACTTGCAC (SEQ ID NO: 913) GCTTACTGTCCACCTGAAGGATTAGA (SEQ ID NO: 914) hCV30830514  A/G CATAGAGTATACCATGTTTTGAGACT (SEQ ID NO: 915) ATAGAGTATACCATGTTTTGAGACC (SEQ ID NO: 916) GCGGCTATGTATTATAGTTGTTAAGCATGA (SEQ ID NO: 917) hCV30830536  G/T TGCATGAGGTTTACATTCAGATC (SEQ ID NO: 918) TTGCATGAGGTTTACATTCAGATA (SEQ ID NO: 919) GAACACTTTAGGAATGGATGGTTTCAACT (SEQ ID NO: 920) hCV30830538  A/C GGTATGATGCCCTTGAGAA (SEQ ID NO: 921) GGTATGATGCCCTTGAGAC (SEQ ID NO: 922) TTTCCCAACCTGGCCATTGAC (SEQ ID NO: 923) hCV30830539  C/T GTGACTTGAGTTTCTCAGGAG (SEQ ID NO: 924) GTGACTTGAGTTTCTCAGGAA (SEQ ID NO: 925) CTCATCTTACCACTGATAACACAGTTCT (SEQ ID NO: 926) hCV30830568  C/T CAGACGCATGCCACTAC (SEQ ID NO: 927) ACAGACGCATGCCACTAT (SEQ ID NO: 928) ACTTGAACCCAGGAGTTCGAGAATA (SEQ ID NO: 929) hCV30830600  A/T AGCAGAAGACTTGATGACCTATTA (SEQ ID NO: 930) GCAGAAGACTTGATGACCTATTT (SEQ ID NO: 931) GCCCCAACTGTATTATGCAGTTTGA (SEQ ID NO: 932) hCV30830611  A/C GACCCAAACTATTCACATGGAT (SEQ ID NO: 933) GACCCAAACTATTCACATGGAG (SEQ ID NO: 934) CCAGAGGTCGCCACTGTTAAC (SEQ ID NO: 935) hCV30830638  C/T CATAGTTGTTCTCTCTGATCCTC (SEQ ID NO: 936) CATAGTTGTTCTCTCTGATCCTT (SEQ ID NO: 937) TCCTCTGCTGCAATCTCCTCATAG (SEQ ID NO: 938) hCV30830641  C/T GGCTCATAACTGTAGTCTTAGC (SEQ ID NO: 939) TGGCTCATAACTGTAGTCTTAGT (SEQ ID NO: 940) GCTGCAGTGCATTGGTACAA (SEQ ID NO: 941) hCV30830652  C/T AATCTATGGCAGTTGCCC (SEQ ID NO: 942) GAATCTATGGCAGTTGCCT (SEQ ID NO: 943) TCTGGGGTTGTCAAATTGAGAGACAT (SEQ ID NO: 944) hCV30830668  C/T GTGTACCATACTTATTCTCCCG (SEQ ID NO: 945) TGTGTACCATACTTATTCTCCCA (SEQ ID NO: 946) GAGATGGGTGGTATGGATGGAATGA (SEQ ID NO: 947) hCV30830686  C/T ACTGTAGTAGCCCAGTATCAAG (SEQ ID NO: 948) ACTGTAGTAGCCCAGTATCAAA (SEQ ID NO: 949) CCAACATAAGGCTAAGGCAAACACT (SEQ ID NO: 950) hCV30830725 A/T ATCCTTTTCCCGTAGAATTGAAT (SEQ ID NO: 951) ATCCTTTTCCCGTAGAATTGAAA (SEQ ID NO: 952) GAAGATCTCAGGGGCCTCTAAGAG (SEQ ID NO: 953) hCV3121923 A/G CTCCTAACTGGTCCACTCAT (SEQ ID NO: 954) TCCTAACTGGTCCACTCAC (SEQ ID NO: 955) GCTGGGTTTTGATGGGGAAGTAG (SEQ ID NO: 956) hCV578218 G/T CCCATACTCCACTAACAAGGAC (SEQ ID NO: 957) CCCATACTCCACTAACAAGGAA (SEQ ID NO: 958) CTTGCAGAATGTCTTAGGGGACTAGT (SEQ ID NO: 959) hCV578219 C/T GCCTTTGGGAAACGCC (SEQ ID NO: 960) GCCTTTGGGAAACGCT (SEQ ID NO: 961) CCACCCCTTTGAATCCCATACTC (SEQ ID NO: 962) hCV578224 C/T GGTTTTGCACAAGGCATG (SEQ ID NO: 963) GGGTTTTGCACAAGGCATA (SEQ ID NO: 964) GCACATGTGCAGGATGAGAAAGATAC (SEQ ID NO: 965) hCV7577155 C/G GACAGATGAGAAGTCACTTCAAC (SEQ ID NO: 966) GACAGATGAGAAGTCACTTCAAG (SEQ ID NO: 967) GCTGGGATTACATGCATGAGTCA (SEQ ID NO: 968) hCV7577254 C/T TCCTTATAAAATCAGACAGTTCTGC (SEQ ID NO: 969) TCCTTATAAAATCAGACAGTTCTGT (SEQ ID NO: 970) GCCTCAAAGGGAAACAAGCCTTAAT (SEQ ID NO: 971) hCV7577271 A/G TCTTCACAACAGCAGATACCA (SEQ ID NO: 972) CTTCACAACAGCAGATACCG (SEQ ID NO: 973) CACCACCCTACTTACTAGCTTTGAGTA (SEQ ID NO: 974) hCV7577296 C/T TATTTTGGTTTCTTGGCTCATATAAG (SEQ ID NO: 975) TTATTTTGGTTTCTTGGCTCATATAAA AGACCCAGTGATTCCAACCAATATCAT (SEQ ID NO: 977) (SEQ ID NO: 976) hCV7577317 C/G GTAAAATTTAAAAGAACTGAAATGGAAGAG GTAAAATTTAAAAGAACTGAAATGGAAGAC GAAGAATTATATCACTGCTTCTCATGAATCTCAC (SEQ ID NO: 978) (SEQ ID NO: 979) (SEQ ID NO 980) hCV7577337 A/G CTCCAGTGTGTCTCATTTGT (SEQ ID NO: 981) TCCAGTGTGTCTCATTTGC (SEQ ID NO: 982) GAGATTCAGGGACGGAAAGAAGC (SEQ ID NO: 983) hCV7577344 A/T TTCCCTTCCAGATAACATCCA (SEQ ID NO: 984) TTCCCTTCCAGATAACATCCT (SEQ ID NO: 985) CTGTAAGGAGCCCTAGGAAGAATTATG (SEQ ID NO: 986) hCV8605400 A/C GACTCCAATGTCATGTTCTTTGA (SEQ ID NO: 987) CTCCAATGTCATGTTCTTTGC (SEQ ID NO: 988) GTACCCACTCAGGAGCTCTTAGT (SEQ ID NO: 989) hCV8780517 A/G GAGACTCCCATCACAGAGT (SEQ ID NO: 990) AGACTCCCATCACAGAGC (SEQ ID NO: 991) ACCAAACCCATCTCCACTTTACAGT (SEQ ID NO: 992) hCV8780962 A/G TGGGATGAGCAATCCTGTTAT (SEQ ID NO: 993) GGGATGAGCAATCCTGTTAC (SEQ ID NO: 994) ACCTCATTAGGCCTTGTGCTATCT (SEQ ID NO: 995) hCV8780967 C/T ACAGCAACCTGAAAGATTACAG (SEQ ID NO: 996) ACAGCAACCTGAAAGATTACAA (SEQ ID NO: 997) GTTTTGTGTGTGTGTGTGTGTGAT (SEQ ID NO: 998) hCV8780973 A/G CAAGCATCCTGACTTCATTTAGA (SEQ ID NO: 999) AAGCATCCTGACTTCATTTAGG (SEQ ID NO: 1000) GAGACCTTACTTTTAGGACACCGTAGTT (SEQ ID NO: 1001) hDV70729405 C/T CTAACCACAACCTACCACAC (SEQ ID NO: 1002) CTAACCACAACCTACCACAT (SEQ ID NO: 1003) TTGGAACCTTCGATTCTCCAGATCT (SEQ ID NO: 1004)

TABLE 4 Interrogated SNP Interrogated rs LD SNP LD SNP rs Power Threshold r² r² hCV11266229 rs10435844 hCV11266268 rs10760121 0.51 0.411716825 0.9666 hCV11266229 rs10435844 hCV11720350 rs2057469 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV11720413 rs1930782 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV11720414 rs1930781 0.51 0.411716825 1 hCV11266229 rs10435844 hCV15849105 rs2900185 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV15849116 rs2900180 0.51 0.411716825 1 hCV11266229 rs10435844 hCV15870898 rs2072438 0.51 0.411716825 0.6467 hCV11266229 rs10435844 hCV16124825 rs2109895 0.51 0.411716825 1 hCV11266229 rs10435844 hCV16175379 rs2239657 0.51 0.411716825 0.9664 hCV11266229 rs10435844 hCV16234795 rs2416804 0.51 0.411716825 0.6341 hCV11266229 rs10435844 hCV16234838 rs2416819 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV16234840 rs2416817 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV1632195 rs1998505 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV1761888 rs1953126 0.51 0.411716825 0.9666 hCV11266229 rs10435844 hCV1761891 rs1930778 0.51 0.411716825 0.9602 hCV11266229 rs10435844 hCV1761894 rs1609810 0.51 0.411716825 0.9609 hCV11266229 rs10435844 hCV2359565 rs1014530 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV25613469 rs10760157 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV25751916 rs10985070 0.51 0.411716825 0.6467 hCV11266229 rs10435844 hCV25771057 rs10760150 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV2783582 rs10818482 0.51 0.411716825 0.6467 hCV11266229 rs10435844 hCV2783586 rs2270231 0.51 0.411716825 0.9666 hCV11266229 rs10435844 hCV2783589 rs881375 0.51 0.411716825 0.9666 hCV11266229 rs10435844 hCV2783590 rs6478486 0.51 0.411716825 0.9666 hCV11266229 rs10435844 hCV2783591 rs1468671 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783593 rs1548783 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783597 rs1860824 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783599 rs7046108 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783604 rs10760126 0.51 0.411716825 0.6875 hCV11266229 rs10435844 hCV2783607 rs9886724 0.51 0.411716825 0.6785 hCV11266229 rs10435844 hCV2783608 rs4836834 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV2783609 rs2241003 0.51 0.411716825 0.9321 hCV11266229 rs10435844 hCV2783611 rs10435843 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783618 rs2239658 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783620 rs7021880 0.51 0.411716825 0.9301 hCV11266229 rs10435844 hCV2783621 rs2416805 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783622 rs758959 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783625 rs10118357 0.51 0.411716825 0.6645 hCV11266229 rs10435844 hCV2783630 rs2269060 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV2783633 rs7021049 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV2783634 rs1014529 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783635 rs1930780 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783638 rs3761846 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV2783640 rs3761847 0.51 0.411716825 0.6341 hCV11266229 rs10435844 hCV2783641 rs2416806 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783647 rs10739580 0.51 0.411716825 1 hCV11266229 rs10435844 hCV2783650 rs10760129 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV2783653 rs10760130 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV2783655 rs10818488 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV2783656 rs4837804 0.51 0.411716825 0.8956 hCV11266229 rs10435844 hCV2783659 rs7039505 0.51 0.411716825 1 hCV11266229 rs10435844 hCV27912350 rs4837808 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV27912351 rs4837809 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV29005923 rs6478494 0.51 0.411716825 0.4238 hCV11266229 rs10435844 hCV29005924 rs7031128 0.51 0.411716825 0.4264 hCV11266229 rs10435844 hCV29005976 rs7037195 0.51 0.411716825 0.6687 hCV11266229 rs10435844 hCV29005978 rs7021206 0.51 0.411716825 1 hCV11266229 rs10435844 hCV29006006 rs7034390 0.51 0.411716825 0.9666 hCV11266229 rs10435844 hCV30059070 rs10156413 0.51 0.411716825 0.5258 hCV11266229 rs10435844 hCV3045792 rs6478499 0.51 0.411716825 0.4879 hCV11266229 rs10435844 hCV3045801 rs2057465 0.51 0.411716825 0.4332 hCV11266229 rs10435844 hCV30563729 rs9299273 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV30830414 rs7871371 0.51 0.411716825 0.417 hCV11266229 rs10435844 hCV30830468 rs10818507 0.51 0.411716825 0.4539 hCV11266229 rs10435844 hCV30830473 rs7036649 0.51 0.411716825 0.4705 hCV11266229 rs10435844 hCV30830475 rs10733652 0.51 0.411716825 0.4269 hCV11266229 rs10435844 hCV30830484 rs10818508 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV30830486 rs10760149 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV30830503 rs4837811 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV30830512 rs10818512 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV30830521 rs10818513 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV30830536 rs7047038 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV30830638 rs10985073 0.51 0.411716825 0.6467 hCV11266229 rs10435844 hCV30830725 rs7864019 0.51 0.411716825 1 hCV11266229 rs10435844 hCV30830832 rs10733648 0.51 0.411716825 1 hCV11266229 rs10435844 hCV30830909 rs11794516 0.51 0.411716825 0.6467 hCV11266229 rs10435844 hCV7577250 rs942153 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV7577271 rs1535655 0.51 0.411716825 0.4465 hCV11266229 rs10435844 hCV7577287 rs1323478 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV7577296 rs1407910 0.51 0.411716825 0.4708 hCV11266229 rs10435844 hCV7577344 rs876445 0.51 0.411716825 1 hCV11720383 rs1951784 hCV11720402 rs17611 0.51 0.849855381 0.9293 hCV11720383 rs1951784 hCV15751718 rs2296078 0.51 0.849855381 0.9649 hCV11720383 rs1951784 hCV15755658 rs2300934 0.51 0.849855381 0.8947 hCV11720383 rs1951784 hCV16234785 rs2416811 0.51 0.849855381 0.9293 hCV11720383 rs1951784 hCV1632190 rs10760146 0.51 0.849855381 1 hCV11720383 rs1951784 hCV2359571 rs25681 0.51 0.849855381 0.9293 hCV11720383 rs1951784 hCV25968825 rs10818504 0.51 0.849855381 1 hCV11720383 rs1951784 hCV26144282 rs10818499 0.51 0.849855381 0.9293 hCV11720383 rs1951784 hCV26144291 rs4570235 0.51 0.849855381 0.9293 hCV11720383 rs1951784 hCV26144296 rs10760143 0.51 0.849855381 1 hCV11720383 rs1951784 hCV27476319 rs3747843 0.51 0.849855381 0.9649 hCV11720383 rs1951784 hCV2783711 rs10733650 0.51 0.849855381 0.9293 hCV11720383 rs1951784 hCV29005933 rs7042135 0.51 0.849855381 0.8947 hCV11720383 rs1951784 hCV29005936 rs6478498 0.51 0.849855381 0.8947 hCV11720383 rs1951784 hCV29734592 rs10435889 0.51 0.849855381 0.9272 hCV11720383 rs1951784 hCV29824827 rs9657673 0.51 0.849855381 1 hCV11720383 rs1951784 hCV30041036 rs10156476 0.51 0.849855381 1 hCV11720383 rs1951784 hCV30167357 rs7022941 0.51 0.849855381 1 hCV11720383 rs1951784 hCV3045797 rs7036541 0.51 0.849855381 1 hCV11720383 rs1951784 hCV3045800 rs3736855 0.51 0.849855381 1 hCV11720383 rs1951784 hCV3045804 rs2057467 0.51 0.849855381 0.9484 hCV11720383 rs1951784 hCV3045808 rs10818516 0.51 0.849855381 0.9294 hCV11720383 rs1951784 hCV3045810 rs2209076 0.51 0.849855381 0.9314 hCV11720383 rs1951784 hCV30830415 rs7855998 0.51 0.849855381 0.8947 hCV11720383 rs1951784 hCV30830427 rs10760142 0.51 0.849855381 0.8947 hCV11720383 rs1951784 hCV30830440 rs10760144 0.51 0.849855381 1 hCV11720383 rs1951784 hCV30830506 rs10760151 0.51 0.849855381 1 hCV11720383 rs1951784 hCV30830537 rs10818515 0.51 0.849855381 0.9646 hCV11720383 rs1951784 hCV30830539 rs10760153 0.51 0.849855381 0.9642 hCV11720383 rs1951784 hCV30830540 rs10760154 0.51 0.849855381 0.9649 hCV11720383 rs1951784 hCV30830541 rs10760155 0.51 0.849855381 0.9649 hCV11720383 rs1951784 hCV30830542 rs10760156 0.51 0.849855381 0.9628 hCV11720383 rs1951784 hCV7577235 rs1052508 0.51 0.849855381 0.9649 hCV11720383 rs1951784 hCV7577248 rs1359086 0.51 0.849855381 0.9314 hCV11720383 rs1951784 hCV7577249 rs1359085 0.51 0.849855381 0.9649 hCV11720383 rs1951784 hCV7577337 rs993247 0.51 0.849855381 0.9293 hCV11720402 rs17611 hCV11720383 rs1951784 0.51 0.853213654 0.9293 hCV11720402 rs17611 hCV15751718 rs2296078 0.51 0.853213654 0.8957 hCV11720402 rs17611 hCV15755658 rs2300934 0.51 0.853213654 0.9646 hCV11720402 rs17611 hCV16234785 rs2416811 0.51 0.853213654 1 hCV11720402 rs17611 hCV1632190 rs10760146 0.51 0.853213654 0.9293 hCV11720402 rs17611 hCV2359571 rs25681 0.51 0.853213654 1 hCV11720402 rs17611 hCV25968825 rs10818504 0.51 0.853213654 0.9293 hCV11720402 rs17611 hCV26144282 rs10818499 0.51 0.853213654 1 hCV11720402 rs17611 hCV26144291 rs4570235 0.51 0.853213654 1 hCV11720402 rs17611 hCV26144296 rs10760143 0.51 0.853213654 0.9279 hCV11720402 rs17611 hCV27476319 rs3747843 0.51 0.853213654 0.8957 hCV11720402 rs17611 hCV2783711 rs10733650 0.51 0.853213654 1 hCV11720402 rs17611 hCV29005933 rs7042135 0.51 0.853213654 0.9646 hCV11720402 rs17611 hCV29005936 rs6478498 0.51 0.853213654 0.9646 hCV11720402 rs17611 hCV29734592 rs10435889 0.51 0.853213654 1 hCV11720402 rs17611 hCV29824827 rs9657673 0.51 0.853213654 0.9251 hCV11720402 rs17611 hCV30041036 rs10156476 0.51 0.853213654 0.9286 hCV11720402 rs17611 hCV30167357 rs7022941 0.51 0.853213654 0.9642 hCV11720402 rs17611 hCV3045797 rs7036541 0.51 0.853213654 0.9272 hCV11720402 rs17611 hCV3045800 rs3736855 0.51 0.853213654 0.9293 hCV11720402 rs17611 hCV3045808 rs10818516 0.51 0.853213654 0.8595 hCV11720402 rs17611 hCV3045810 rs2209076 0.51 0.853213654 0.8635 hCV11720402 rs17611 hCV30830340 rs10760134 0.51 0.853213654 0.8956 hCV11720402 rs17611 hCV30830341 rs7040033 0.51 0.853213654 0.8956 hCV11720402 rs17611 hCV30830415 rs7855998 0.51 0.853213654 0.9646 hCV11720402 rs17611 hCV30830427 rs10760142 0.51 0.853213654 0.9646 hCV11720402 rs17611 hCV30830440 rs10760144 0.51 0.853213654 0.9293 hCV11720402 rs17611 hCV30830506 rs10760151 0.51 0.853213654 0.9293 hCV11720402 rs17611 hCV30830537 rs10818515 0.51 0.853213654 0.8946 hCV11720402 rs17611 hCV30830539 rs10760153 0.51 0.853213654 0.9287 hCV11720402 rs17611 hCV30830540 rs10760154 0.51 0.853213654 0.8956 hCV11720402 rs17611 hCV30830541 rs10760155 0.51 0.853213654 0.8957 hCV11720402 rs17611 hCV30830542 rs10760156 0.51 0.853213654 0.8894 hCV11720402 rs17611 hCV7577235 rs1052508 0.51 0.853213654 0.8957 hCV11720402 rs17611 hCV7577248 rs1359086 0.51 0.853213654 0.8635 hCV11720402 rs17611 hCV7577249 rs1359085 0.51 0.853213654 0.8957 hCV11720402 rs17611 hCV7577337 rs993247 0.51 0.853213654 1 hCV11720413 rs1930782 hCV11266229 rs10435844 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV11266268 rs10760121 0.51 0.320507332 0.6344 hCV11720413 rs1930782 hCV11720351 rs1885995 0.51 0.320507332 0.472 hCV11720413 rs1930782 hCV11720402 rs17611 0.51 0.320507332 0.3301 hCV11720413 rs1930782 hCV11720414 rs1930781 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV1452630 rs10818476 0.51 0.320507332 0.3495 hCV11720413 rs1930782 hCV1452651 rs3793638 0.51 0.320507332 0.3281 hCV11720413 rs1930782 hCV1452652 rs1060817 0.51 0.320507332 0.3281 hCV11720413 rs1930782 hCV1452665 rs4837796 0.51 0.320507332 0.3495 hCV11720413 rs1930782 hCV15751717 rs2296077 0.51 0.320507332 0.4129 hCV11720413 rs1930782 hCV15751719 rs2146838 0.51 0.320507332 0.472 hCV11720413 rs1930782 hCV15757738 rs2302498 0.51 0.320507332 0.4266 hCV11720413 rs1930782 hCV15849116 rs2900180 0.51 0.320507332 0.6587 hCV11720413 rs1930782 hCV15870898 rs2072438 0.51 0.320507332 0.9671 hCV11720413 rs1930782 hCV16124825 rs2109895 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV16175379 rs2239657 0.51 0.320507332 0.6463 hCV11720413 rs1930782 hCV16234785 rs2416811 0.51 0.320507332 0.3301 hCV11720413 rs1930782 hCV16234795 rs2416804 0.51 0.320507332 0.9672 hCV11720413 rs1930782 hCV1761881 rs3933326 0.51 0.320507332 0.3254 hCV11720413 rs1930782 hCV1761888 rs1953126 0.51 0.320507332 0.6344 hCV11720413 rs1930782 hCV1761891 rs1930778 0.51 0.320507332 0.5775 hCV11720413 rs1930782 hCV1761894 rs1609810 0.51 0.320507332 0.6068 hCV11720413 rs1930782 hCV22272588 rs10760117 0.51 0.320507332 0.3495 hCV11720413 rs1930782 hCV2359565 rs1014530 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2359571 rs25681 0.51 0.320507332 0.3301 hCV11720413 rs1930782 hCV25751916 rs10985070 0.51 0.320507332 0.9671 hCV11720413 rs1930782 hCV26144282 rs10818499 0.51 0.320507332 0.3301 hCV11720413 rs1930782 hCV26144291 rs4570235 0.51 0.320507332 0.3301 hCV11720413 rs1930782 hCV26144307 rs1016468 0.51 0.320507332 0.472 hCV11720413 rs1930782 hCV26144332 rs4837813 0.51 0.320507332 0.4513 hCV11720413 rs1930782 hCV2783582 rs10818482 0.51 0.320507332 0.9671 hCV11720413 rs1930782 hCV2783586 rs2270231 0.51 0.320507332 0.6344 hCV11720413 rs1930782 hCV2783589 rs881375 0.51 0.320507332 0.6344 hCV11720413 rs1930782 hCV2783590 rs6478486 0.51 0.320507332 0.6344 hCV11720413 rs1930782 hCV2783591 rs1468671 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783593 rs1548783 0.51 0.320507332 0.6645 hCV11720413 rs1930782 hCV2783597 rs1860824 0.51 0.320507332 0.6581 hCV11720413 rs1930782 hCV2783599 rs7046108 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783604 rs10760126 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783607 rs9886724 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783608 rs4836834 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783609 rs2241003 0.51 0.320507332 0.7074 hCV11720413 rs1930782 hCV2783611 rs10435843 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783618 rs2239658 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783620 rs7021880 0.51 0.320507332 0.6088 hCV11720413 rs1930782 hCV2783621 rs2416805 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783622 rs758959 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783625 rs10118357 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783630 rs2269060 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783633 rs7021049 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783634 rs1014529 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783635 rs1930780 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783638 rs3761846 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783640 rs3761847 0.51 0.320507332 0.9672 hCV11720413 rs1930782 hCV2783641 rs2416806 0.51 0.320507332 0.6594 hCV11720413 rs1930782 hCV2783647 rs10739580 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV2783650 rs10760129 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783653 rs10760130 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783655 rs10818488 0.51 0.320507332 1 hCV11720413 rs1930782 hCV2783656 rs4837804 0.51 0.320507332 0.775 hCV11720413 rs1930782 hCV2783659 rs7039505 0.51 0.320507332 0.6562 hCV11720413 rs1930782 hCV2783711 rs10733650 0.51 0.320507332 0.3723 hCV11720413 rs1930782 hCV2783718 rs10818500 0.51 0.320507332 0.6661 hCV11720413 rs1930782 hCV29005955 rs7036980 0.51 0.320507332 0.4056 hCV11720413 rs1930782 hCV29005976 rs7037195 0.51 0.320507332 1 hCV11720413 rs1930782 hCV29005978 rs7021206 0.51 0.320507332 0.7031 hCV11720413 rs1930782 hCV29006006 rs7034390 0.51 0.320507332 0.6344 hCV11720413 rs1930782 hCV29879049 rs9792437 0.51 0.320507332 0.4468 hCV11720413 rs1930782 hCV3045812 rs7030849 0.51 0.320507332 0.4468 hCV11720413 rs1930782 hCV30829523 rs12343516 0.51 0.320507332 0.3281 hCV11720413 rs1930782 hCV30830319 rs7037673 0.51 0.320507332 0.517 hCV11720413 rs1930782 hCV30830325 rs10818494 0.51 0.320507332 0.4154 hCV11720413 rs1930782 hCV30830340 rs10760134 0.51 0.320507332 0.3949 hCV11720413 rs1930782 hCV30830341 rs7040033 0.51 0.320507332 0.3949 hCV11720413 rs1930782 hCV30830419 rs10985140 0.51 0.320507332 0.6317 hCV11720413 rs1930782 hCV30830474 rs10739590 0.51 0.320507332 0.5169 hCV11720413 rs1930782 hCV30830638 rs10985073 0.51 0.320507332 0.9671 hCV11720413 rs1930782 hCV30830725 rs7864019 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV30830832 rs10733648 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV30830909 rs11794516 0.51 0.320507332 0.9671 hCV11720413 rs1930782 hCV7577254 rs942152 0.51 0.320507332 0.3797 hCV11720413 rs1930782 hCV7577317 rs1323472 0.51 0.320507332 0.6604 hCV11720413 rs1930782 hCV7577331 rs1468673 0.51 0.320507332 0.6604 hCV11720413 rs1930782 hCV7577337 rs993247 0.51 0.320507332 0.3301 hCV11720413 rs1930782 hCV7577344 rs876445 0.51 0.320507332 0.6687 hCV11720413 rs1930782 hCV782875 rs746182 0.51 0.320507332 0.4513 hCV11720414 rs1930781 hCV11266229 rs10435844 0.51 0.412311868 1 hCV11720414 rs1930781 hCV11266268 rs10760121 0.51 0.412311868 0.9666 hCV11720414 rs1930781 hCV11720350 rs2057469 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV11720413 rs1930782 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV15849105 rs2900185 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV15849116 rs2900180 0.51 0.412311868 1 hCV11720414 rs1930781 hCV15870898 rs2072438 0.51 0.412311868 0.6467 hCV11720414 rs1930781 hCV16124825 rs2109895 0.51 0.412311868 1 hCV11720414 rs1930781 hCV16175379 rs2239657 0.51 0.412311868 0.9664 hCV11720414 rs1930781 hCV16234795 rs2416804 0.51 0.412311868 0.6341 hCV11720414 rs1930781 hCV16234838 rs2416819 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV16234840 rs2416817 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV1632195 rs1998505 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV1761888 rs1953126 0.51 0.412311868 0.9666 hCV11720414 rs1930781 hCV1761891 rs1930778 0.51 0.412311868 0.9602 hCV11720414 rs1930781 hCV1761894 rs1609810 0.51 0.412311868 0.9609 hCV11720414 rs1930781 hCV2359565 rs1014530 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV25613469 rs10760157 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV25751916 rs10985070 0.51 0.412311868 0.6467 hCV11720414 rs1930781 hCV25771057 rs10760150 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV2783582 rs10818482 0.51 0.412311868 0.6467 hCV11720414 rs1930781 hCV2783586 rs2270231 0.51 0.412311868 0.9666 hCV11720414 rs1930781 hCV2783589 rs881375 0.51 0.412311868 0.9666 hCV11720414 rs1930781 hCV2783590 rs6478486 0.51 0.412311868 0.9666 hCV11720414 rs1930781 hCV2783591 rs1468671 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783593 rs1548783 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783597 rs1860824 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783599 rs7046108 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783604 rs10760126 0.51 0.412311868 0.6875 hCV11720414 rs1930781 hCV2783607 rs9886724 0.51 0.412311868 0.6785 hCV11720414 rs1930781 hCV2783608 rs4836834 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV2783609 rs2241003 0.51 0.412311868 0.9321 hCV11720414 rs1930781 hCV2783611 rs10435843 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783618 rs2239658 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783620 rs7021880 0.51 0.412311868 0.9301 hCV11720414 rs1930781 hCV2783621 rs2416805 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783622 rs758959 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783625 rs10118357 0.51 0.412311868 0.6645 hCV11720414 rs1930781 hCV2783630 rs2269060 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV2783633 rs7021049 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV2783634 rs1014529 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783635 rs1930780 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783638 rs3761846 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV2783640 rs3761847 0.51 0.412311868 0.6341 hCV11720414 rs1930781 hCV2783641 rs2416806 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783647 rs10739580 0.51 0.412311868 1 hCV11720414 rs1930781 hCV2783650 rs10760129 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV2783653 rs10760130 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV2783655 rs10818488 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV2783656 rs4837804 0.51 0.412311868 0.8956 hCV11720414 rs1930781 hCV2783659 rs7039505 0.51 0.412311868 1 hCV11720414 rs1930781 hCV27912350 rs4837808 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV27912351 rs4837809 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV29005923 rs6478494 0.51 0.412311868 0.4238 hCV11720414 rs1930781 hCV29005924 rs7031128 0.51 0.412311868 0.4264 hCV11720414 rs1930781 hCV29005976 rs7037195 0.51 0.412311868 0.6687 hCV11720414 rs1930781 hCV29005978 rs7021206 0.51 0.412311868 1 hCV11720414 rs1930781 hCV29006006 rs7034390 0.51 0.412311868 0.9666 hCV11720414 rs1930781 hCV30059070 rs10156413 0.51 0.412311868 0.5258 hCV11720414 rs1930781 hCV3045792 rs6478499 0.51 0.412311868 0.4879 hCV11720414 rs1930781 hCV3045801 rs2057465 0.51 0.412311868 0.4332 hCV11720414 rs1930781 hCV30563729 rs9299273 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV30830414 rs7871371 0.51 0.412311868 0.417 hCV11720414 rs1930781 hCV30830468 rs10818507 0.51 0.412311868 0.4539 hCV11720414 rs1930781 hCV30830473 rs7036649 0.51 0.412311868 0.4705 hCV11720414 rs1930781 hCV30830475 rs10733652 0.51 0.412311868 0.4269 hCV11720414 rs1930781 hCV30830484 rs10818508 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV30830486 rs10760149 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV30830503 rs4837811 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV30830512 rs10818512 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV30830521 rs10818513 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV30830536 rs7047038 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV30830638 rs10985073 0.51 0.412311868 0.6467 hCV11720414 rs1930781 hCV30830725 rs7864019 0.51 0.412311868 1 hCV11720414 rs1930781 hCV30830832 rs10733648 0.51 0.412311868 1 hCV11720414 rs1930781 hCV30830909 rs11794516 0.51 0.412311868 0.6467 hCV11720414 rs1930781 hCV7577250 rs942153 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV7577271 rs1535655 0.51 0.412311868 0.4465 hCV11720414 rs1930781 hCV7577287 rs1323478 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV7577296 rs1407910 0.51 0.412311868 0.4708 hCV11720414 rs1930781 hCV7577344 rs876445 0.51 0.412311868 1 hCV15849116 rs2900180 hCV11266229 rs10435844 0.51 0.548091403 1 hCV15849116 rs2900180 hCV11266268 rs10760121 0.51 0.548091403 0.9622 hCV15849116 rs2900180 hCV11720413 rs1930782 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV11720414 rs1930781 0.51 0.548091403 1 hCV15849116 rs2900180 hCV15870898 rs2072438 0.51 0.548091403 0.6342 hCV15849116 rs2900180 hCV16124825 rs2109895 0.51 0.548091403 1 hCV15849116 rs2900180 hCV16175379 rs2239657 0.51 0.548091403 0.962 hCV15849116 rs2900180 hCV16234795 rs2416804 0.51 0.548091403 0.6181 hCV15849116 rs2900180 hCV1761888 rs1953126 0.51 0.548091403 0.9622 hCV15849116 rs2900180 hCV1761891 rs1930778 0.51 0.548091403 0.9553 hCV15849116 rs2900180 hCV1761894 rs1609810 0.51 0.548091403 0.9559 hCV15849116 rs2900180 hCV2359565 rs1014530 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV25751916 rs10985070 0.51 0.548091403 0.6342 hCV15849116 rs2900180 hCV2783582 rs10818482 0.51 0.548091403 0.6342 hCV15849116 rs2900180 hCV2783586 rs2270231 0.51 0.548091403 0.9622 hCV15849116 rs2900180 hCV2783589 rs881375 0.51 0.548091403 0.9622 hCV15849116 rs2900180 hCV2783590 rs6478486 0.51 0.548091403 0.9622 hCV15849116 rs2900180 hCV2783591 rs1468671 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783593 rs1548783 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783597 rs1860824 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783599 rs7046108 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783604 rs10760126 0.51 0.548091403 0.6795 hCV15849116 rs2900180 hCV2783607 rs9886724 0.51 0.548091403 0.669 hCV15849116 rs2900180 hCV2783608 rs4836834 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783609 rs2241003 0.51 0.548091403 0.9232 hCV15849116 rs2900180 hCV2783611 rs10435843 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783618 rs2239658 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783620 rs7021880 0.51 0.548091403 0.9252 hCV15849116 rs2900180 hCV2783621 rs2416805 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783622 rs758959 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783625 rs10118357 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783630 rs2269060 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783633 rs7021049 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783634 rs1014529 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783635 rs1930780 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783638 rs3761846 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783640 rs3761847 0.51 0.548091403 0.6181 hCV15849116 rs2900180 hCV2783641 rs2416806 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783647 rs10739580 0.51 0.548091403 1 hCV15849116 rs2900180 hCV2783650 rs10760129 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783653 rs10760130 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783655 rs10818488 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV2783656 rs4837804 0.51 0.548091403 0.8894 hCV15849116 rs2900180 hCV2783659 rs7039505 0.51 0.548091403 1 hCV15849116 rs2900180 hCV29005976 rs7037195 0.51 0.548091403 0.6587 hCV15849116 rs2900180 hCV29005978 rs7021206 0.51 0.548091403 1 hCV15849116 rs2900180 hCV29006006 rs7034390 0.51 0.548091403 0.9622 hCV15849116 rs2900180 hCV30830638 rs10985073 0.51 0.548091403 0.6342 hCV15849116 rs2900180 hCV30830725 rs7864019 0.51 0.548091403 1 hCV15849116 rs2900180 hCV30830832 rs10733648 0.51 0.548091403 1 hCV15849116 rs2900180 hCV30830909 rs11794516 0.51 0.548091403 0.6342 hCV15849116 rs2900180 hCV7577344 rs876445 0.51 0.548091403 1 hCV15870898 rs2072438 hCV11266229 rs10435844 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV11266268 rs10760121 0.51 0.357983748 0.6691 hCV15870898 rs2072438 hCV11720351 rs1885995 0.51 0.357983748 0.4963 hCV15870898 rs2072438 hCV11720413 rs1930782 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV11720414 rs1930781 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV1452630 rs10818476 0.51 0.357983748 0.3756 hCV15870898 rs2072438 hCV1452665 rs4837796 0.51 0.357983748 0.3756 hCV15870898 rs2072438 hCV15751717 rs2296077 0.51 0.357983748 0.4374 hCV15870898 rs2072438 hCV15751719 rs2146838 0.51 0.357983748 0.4963 hCV15870898 rs2072438 hCV15757738 rs2302498 0.51 0.357983748 0.4505 hCV15870898 rs2072438 hCV15849116 rs2900180 0.51 0.357983748 0.6342 hCV15870898 rs2072438 hCV16124825 rs2109895 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV16175379 rs2239657 0.51 0.357983748 0.625 hCV15870898 rs2072438 hCV16234795 rs2416804 0.51 0.357983748 0.9353 hCV15870898 rs2072438 hCV1761888 rs1953126 0.51 0.357983748 0.6691 hCV15870898 rs2072438 hCV1761891 rs1930778 0.51 0.357983748 0.6222 hCV15870898 rs2072438 hCV1761894 rs1609810 0.51 0.357983748 0.6485 hCV15870898 rs2072438 hCV22272588 rs10760117 0.51 0.357983748 0.3756 hCV15870898 rs2072438 hCV2359565 rs1014530 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV25751916 rs10985070 0.51 0.357983748 1 hCV15870898 rs2072438 hCV26144307 rs1016468 0.51 0.357983748 0.4963 hCV15870898 rs2072438 hCV26144332 rs4837813 0.51 0.357983748 0.4761 hCV15870898 rs2072438 hCV2783582 rs10818482 0.51 0.357983748 1 hCV15870898 rs2072438 hCV2783586 rs2270231 0.51 0.357983748 0.6691 hCV15870898 rs2072438 hCV2783589 rs881375 0.51 0.357983748 0.6691 hCV15870898 rs2072438 hCV2783590 rs6478486 0.51 0.357983748 0.6691 hCV15870898 rs2072438 hCV2783591 rs1468671 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783593 rs1548783 0.51 0.357983748 0.6423 hCV15870898 rs2072438 hCV2783597 rs1860824 0.51 0.357983748 0.6357 hCV15870898 rs2072438 hCV2783599 rs7046108 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783604 rs10760126 0.51 0.357983748 0.9666 hCV15870898 rs2072438 hCV2783607 rs9886724 0.51 0.357983748 1 hCV15870898 rs2072438 hCV2783608 rs4836834 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV2783609 rs2241003 0.51 0.357983748 0.7074 hCV15870898 rs2072438 hCV2783611 rs10435843 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783618 rs2239658 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783620 rs7021880 0.51 0.357983748 0.5878 hCV15870898 rs2072438 hCV2783621 rs2416805 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783622 rs758959 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783625 rs10118357 0.51 0.357983748 0.9665 hCV15870898 rs2072438 hCV2783630 rs2269060 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV2783633 rs7021049 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV2783634 rs1014529 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783635 rs1930780 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783638 rs3761846 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV2783640 rs3761847 0.51 0.357983748 0.9353 hCV15870898 rs2072438 hCV2783641 rs2416806 0.51 0.357983748 0.6594 hCV15870898 rs2072438 hCV2783647 rs10739580 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV2783650 rs10760129 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV2783653 rs10760130 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV2783655 rs10818488 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV2783656 rs4837804 0.51 0.357983748 0.7472 hCV15870898 rs2072438 hCV2783659 rs7039505 0.51 0.357983748 0.6319 hCV15870898 rs2072438 hCV2783711 rs10733650 0.51 0.357983748 0.3903 hCV15870898 rs2072438 hCV2783718 rs10818500 0.51 0.357983748 0.6972 hCV15870898 rs2072438 hCV29005955 rs7036980 0.51 0.357983748 0.4304 hCV15870898 rs2072438 hCV29005976 rs7037195 0.51 0.357983748 0.9671 hCV15870898 rs2072438 hCV29005978 rs7021206 0.51 0.357983748 0.6788 hCV15870898 rs2072438 hCV29006006 rs7034390 0.51 0.357983748 0.6691 hCV15870898 rs2072438 hCV29879049 rs9792437 0.51 0.357983748 0.4711 hCV15870898 rs2072438 hCV3045812 rs7030849 0.51 0.357983748 0.4711 hCV15870898 rs2072438 hCV30830319 rs7037673 0.51 0.357983748 0.5359 hCV15870898 rs2072438 hCV30830325 rs10818494 0.51 0.357983748 0.4346 hCV15870898 rs2072438 hCV30830340 rs10760134 0.51 0.357983748 0.4135 hCV15870898 rs2072438 hCV30830341 rs7040033 0.51 0.357983748 0.4135 hCV15870898 rs2072438 hCV30830419 rs10985140 0.51 0.357983748 0.6598 hCV15870898 rs2072438 hCV30830474 rs10739590 0.51 0.357983748 0.5521 hCV15870898 rs2072438 hCV30830638 rs10985073 0.51 0.357983748 1 hCV15870898 rs2072438 hCV30830725 rs7864019 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV30830832 rs10733648 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV30830909 rs11794516 0.51 0.357983748 1 hCV15870898 rs2072438 hCV7577254 rs942152 0.51 0.357983748 0.4017 hCV15870898 rs2072438 hCV7577317 rs1323472 0.51 0.357983748 0.6896 hCV15870898 rs2072438 hCV7577331 rs1468673 0.51 0.357983748 0.6896 hCV15870898 rs2072438 hCV7577344 rs876445 0.51 0.357983748 0.6467 hCV15870898 rs2072438 hCV782875 rs746182 0.51 0.357983748 0.4761 hCV16175379 rs2239657 hCV11266229 rs10435844 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV11266268 rs10760121 0.51 0.423423973 0.9341 hCV16175379 rs2239657 hCV11720413 rs1930782 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV11720414 rs1930781 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV15849105 rs2900185 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV15849116 rs2900180 0.51 0.423423973 0.962 hCV16175379 rs2239657 hCV15870898 rs2072438 0.51 0.423423973 0.625 hCV16175379 rs2239657 hCV16124825 rs2109895 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV16234795 rs2416804 0.51 0.423423973 0.6112 hCV16175379 rs2239657 hCV16234840 rs2416817 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV1632195 rs1998505 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV1761888 rs1953126 0.51 0.423423973 0.9341 hCV16175379 rs2239657 hCV1761891 rs1930778 0.51 0.423423973 0.9602 hCV16175379 rs2239657 hCV1761894 rs1609810 0.51 0.423423973 0.9609 hCV16175379 rs2239657 hCV2359565 rs1014530 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV25751916 rs10985070 0.51 0.423423973 0.625 hCV16175379 rs2239657 hCV25771057 rs10760150 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV2783582 rs10818482 0.51 0.423423973 0.625 hCV16175379 rs2239657 hCV2783586 rs2270231 0.51 0.423423973 0.9341 hCV16175379 rs2239657 hCV2783589 rs881375 0.51 0.423423973 0.9341 hCV16175379 rs2239657 hCV2783590 rs6478486 0.51 0.423423973 0.9341 hCV16175379 rs2239657 hCV2783591 rs1468671 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783593 rs1548783 0.51 0.423423973 0.966 hCV16175379 rs2239657 hCV2783597 rs1860824 0.51 0.423423973 0.9647 hCV16175379 rs2239657 hCV2783599 rs7046108 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783604 rs10760126 0.51 0.423423973 0.6641 hCV16175379 rs2239657 hCV2783607 rs9886724 0.51 0.423423973 0.6545 hCV16175379 rs2239657 hCV2783608 rs4836834 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV2783609 rs2241003 0.51 0.423423973 0.8997 hCV16175379 rs2239657 hCV2783611 rs10435843 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783618 rs2239658 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783620 rs7021880 0.51 0.423423973 0.8938 hCV16175379 rs2239657 hCV2783621 rs2416805 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783622 rs758959 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783625 rs10118357 0.51 0.423423973 0.6419 hCV16175379 rs2239657 hCV2783630 rs2269060 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV2783633 rs7021049 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV2783634 rs1014529 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783635 rs1930780 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783638 rs3761846 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV2783640 rs3761847 0.51 0.423423973 0.6112 hCV16175379 rs2239657 hCV2783641 rs2416806 0.51 0.423423973 0.9652 hCV16175379 rs2239657 hCV2783647 rs10739580 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV2783650 rs10760129 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV2783653 rs10760130 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV2783655 rs10818488 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV2783656 rs4837804 0.51 0.423423973 0.8631 hCV16175379 rs2239657 hCV2783659 rs7039505 0.51 0.423423973 1 hCV16175379 rs2239657 hCV27912350 rs4837808 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV27912351 rs4837809 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV29005976 rs7037195 0.51 0.423423973 0.6463 hCV16175379 rs2239657 hCV29005978 rs7021206 0.51 0.423423973 0.9649 hCV16175379 rs2239657 hCV29006006 rs7034390 0.51 0.423423973 0.9341 hCV16175379 rs2239657 hCV30059070 rs10156413 0.51 0.423423973 0.4892 hCV16175379 rs2239657 hCV3045792 rs6478499 0.51 0.423423973 0.4586 hCV16175379 rs2239657 hCV30563729 rs9299273 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV30830468 rs10818507 0.51 0.423423973 0.4248 hCV16175379 rs2239657 hCV30830473 rs7036649 0.51 0.423423973 0.4387 hCV16175379 rs2239657 hCV30830484 rs10818508 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV30830486 rs10760149 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV30830503 rs4837811 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV30830638 rs10985073 0.51 0.423423973 0.625 hCV16175379 rs2239657 hCV30830725 rs7864019 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV30830832 rs10733648 0.51 0.423423973 0.9664 hCV16175379 rs2239657 hCV30830909 rs11794516 0.51 0.423423973 0.625 hCV16175379 rs2239657 hCV7577287 rs1323478 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV7577296 rs1407910 0.51 0.423423973 0.4418 hCV16175379 rs2239657 hCV7577344 rs876445 0.51 0.423423973 0.9664 hCV16234785 rs2416811 hCV11720383 rs1951784 0.51 0.852868152 0.9293 hCV16234785 rs2416811 hCV11720402 rs17611 0.51 0.852868152 1 hCV16234785 rs2416811 hCV15751718 rs2296078 0.51 0.852868152 0.8957 hCV16234785 rs2416811 hCV15755658 rs2300934 0.51 0.852868152 0.9646 hCV16234785 rs2416811 hCV1632190 rs10760146 0.51 0.852868152 0.9293 hCV16234785 rs2416811 hCV2359571 rs25681 0.51 0.852868152 1 hCV16234785 rs2416811 hCV25968825 rs10818504 0.51 0.852868152 0.9293 hCV16234785 rs2416811 hCV26144282 rs10818499 0.51 0.852868152 1 hCV16234785 rs2416811 hCV26144291 rs4570235 0.51 0.852868152 1 hCV16234785 rs2416811 hCV26144296 rs10760143 0.51 0.852868152 0.9279 hCV16234785 rs2416811 hCV27476319 rs3747843 0.51 0.852868152 0.8957 hCV16234785 rs2416811 hCV2783711 rs10733650 0.51 0.852868152 1 hCV16234785 rs2416811 hCV29005933 rs7042135 0.51 0.852868152 0.9646 hCV16234785 rs2416811 hCV29005936 rs6478498 0.51 0.852868152 0.9646 hCV16234785 rs2416811 hCV29734592 rs10435889 0.51 0.852868152 1 hCV16234785 rs2416811 hCV29824827 rs9657673 0.51 0.852868152 0.9251 hCV16234785 rs2416811 hCV30041036 rs10156476 0.51 0.852868152 0.9286 hCV16234785 rs2416811 hCV30167357 rs7022941 0.51 0.852868152 0.9642 hCV16234785 rs2416811 hCV3045797 rs7036541 0.51 0.852868152 0.9272 hCV16234785 rs2416811 hCV3045800 rs3736855 0.51 0.852868152 0.9293 hCV16234785 rs2416811 hCV3045808 rs10818516 0.51 0.852868152 0.8595 hCV16234785 rs2416811 hCV3045810 rs2209076 0.51 0.852868152 0.8635 hCV16234785 rs2416811 hCV30830340 rs10760134 0.51 0.852868152 0.8956 hCV16234785 rs2416811 hCV30830341 rs7040033 0.51 0.852868152 0.8956 hCV16234785 rs2416811 hCV30830415 rs7855998 0.51 0.852868152 0.9646 hCV16234785 rs2416811 hCV30830427 rs10760142 0.51 0.852868152 0.9646 hCV16234785 rs2416811 hCV30830440 rs10760144 0.51 0.852868152 0.9293 hCV16234785 rs2416811 hCV30830506 rs10760151 0.51 0.852868152 0.9293 hCV16234785 rs2416811 hCV30830537 rs10818515 0.51 0.852868152 0.8946 hCV16234785 rs2416811 hCV30830539 rs10760153 0.51 0.852868152 0.9287 hCV16234785 rs2416811 hCV30830540 rs10760154 0.51 0.852868152 0.8956 hCV16234785 rs2416811 hCV30830541 rs10760155 0.51 0.852868152 0.8957 hCV16234785 rs2416811 hCV30830542 rs10760156 0.51 0.852868152 0.8894 hCV16234785 rs2416811 hCV7577235 rs1052508 0.51 0.852868152 0.8957 hCV16234785 rs2416811 hCV7577248 rs1359086 0.51 0.852868152 0.8635 hCV16234785 rs2416811 hCV7577249 rs1359085 0.51 0.852868152 0.8957 hCV16234785 rs2416811 hCV7577337 rs993247 0.51 0.852868152 1 hCV16234795 rs2416804 hCV11266229 rs10435844 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV11266268 rs10760121 0.51 0.321177244 0.6014 hCV16234795 rs2416804 hCV11720351 rs1885995 0.51 0.321177244 0.4991 hCV16234795 rs2416804 hCV11720402 rs17611 0.51 0.321177244 0.3592 hCV16234795 rs2416804 hCV11720413 rs1930782 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV11720414 rs1930781 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV1452630 rs10818476 0.51 0.321177244 0.3275 hCV16234795 rs2416804 hCV1452665 rs4837796 0.51 0.321177244 0.3275 hCV16234795 rs2416804 hCV15751717 rs2296077 0.51 0.321177244 0.4385 hCV16234795 rs2416804 hCV15751719 rs2146838 0.51 0.321177244 0.4991 hCV16234795 rs2416804 hCV15755658 rs2300934 0.51 0.321177244 0.3423 hCV16234795 rs2416804 hCV15757738 rs2302498 0.51 0.321177244 0.4513 hCV16234795 rs2416804 hCV15849116 rs2900180 0.51 0.321177244 0.6181 hCV16234795 rs2416804 hCV15870898 rs2072438 0.51 0.321177244 0.9353 hCV16234795 rs2416804 hCV16124825 rs2109895 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV16175379 rs2239657 0.51 0.321177244 0.6112 hCV16234795 rs2416804 hCV16234785 rs2416811 0.51 0.321177244 0.3592 hCV16234795 rs2416804 hCV1761881 rs3933326 0.51 0.321177244 0.3407 hCV16234795 rs2416804 hCV1761888 rs1953126 0.51 0.321177244 0.6014 hCV16234795 rs2416804 hCV1761891 rs1930778 0.51 0.321177244 0.5354 hCV16234795 rs2416804 hCV1761894 rs1609810 0.51 0.321177244 0.6068 hCV16234795 rs2416804 hCV22272588 rs10760117 0.51 0.321177244 0.3275 hCV16234795 rs2416804 hCV2359565 rs1014530 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2359571 rs25681 0.51 0.321177244 0.3592 hCV16234795 rs2416804 hCV25751916 rs10985070 0.51 0.321177244 0.9353 hCV16234795 rs2416804 hCV25757804 rs4836833 0.51 0.321177244 0.3234 hCV16234795 rs2416804 hCV26144282 rs10818499 0.51 0.321177244 0.3592 hCV16234795 rs2416804 hCV26144291 rs4570235 0.51 0.321177244 0.3592 hCV16234795 rs2416804 hCV26144307 rs1016468 0.51 0.321177244 0.4991 hCV16234795 rs2416804 hCV26144332 rs4837813 0.51 0.321177244 0.476 hCV16234795 rs2416804 hCV2783582 rs10818482 0.51 0.321177244 0.9353 hCV16234795 rs2416804 hCV2783586 rs2270231 0.51 0.321177244 0.6014 hCV16234795 rs2416804 hCV2783589 rs881375 0.51 0.321177244 0.6014 hCV16234795 rs2416804 hCV2783590 rs6478486 0.51 0.321177244 0.6014 hCV16234795 rs2416804 hCV2783591 rs1468671 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783593 rs1548783 0.51 0.321177244 0.6289 hCV16234795 rs2416804 hCV2783597 rs1860824 0.51 0.321177244 0.6215 hCV16234795 rs2416804 hCV2783599 rs7046108 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783604 rs10760126 0.51 0.321177244 0.9666 hCV16234795 rs2416804 hCV2783607 rs9886724 0.51 0.321177244 0.9655 hCV16234795 rs2416804 hCV2783608 rs4836834 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2783609 rs2241003 0.51 0.321177244 0.6714 hCV16234795 rs2416804 hCV2783611 rs10435843 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783618 rs2239658 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783620 rs7021880 0.51 0.321177244 0.5724 hCV16234795 rs2416804 hCV2783621 rs2416805 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783622 rs758959 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783625 rs10118357 0.51 0.321177244 0.9666 hCV16234795 rs2416804 hCV2783630 rs2269060 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2783633 rs7021049 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2783634 rs1014529 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783635 rs1930780 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783638 rs3761846 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2783640 rs3761847 0.51 0.321177244 0.9341 hCV16234795 rs2416804 hCV2783641 rs2416806 0.51 0.321177244 0.6235 hCV16234795 rs2416804 hCV2783647 rs10739580 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV2783650 rs10760129 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2783653 rs10760130 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2783655 rs10818488 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV2783656 rs4837804 0.51 0.321177244 0.7379 hCV16234795 rs2416804 hCV2783659 rs7039505 0.51 0.321177244 0.6146 hCV16234795 rs2416804 hCV2783711 rs10733650 0.51 0.321177244 0.3571 hCV16234795 rs2416804 hCV2783718 rs10818500 0.51 0.321177244 0.6979 hCV16234795 rs2416804 hCV29005933 rs7042135 0.51 0.321177244 0.3423 hCV16234795 rs2416804 hCV29005936 rs6478498 0.51 0.321177244 0.3423 hCV16234795 rs2416804 hCV29005955 rs7036980 0.51 0.321177244 0.4285 hCV16234795 rs2416804 hCV29005976 rs7037195 0.51 0.321177244 0.9672 hCV16234795 rs2416804 hCV29005978 rs7021206 0.51 0.321177244 0.6666 hCV16234795 rs2416804 hCV29006006 rs7034390 0.51 0.321177244 0.6014 hCV16234795 rs2416804 hCV29734592 rs10435889 0.51 0.321177244 0.3475 hCV16234795 rs2416804 hCV29879049 rs9792437 0.51 0.321177244 0.4729 hCV16234795 rs2416804 hCV30167357 rs7022941 0.51 0.321177244 0.3336 hCV16234795 rs2416804 hCV3045812 rs7030849 0.51 0.321177244 0.4729 hCV16234795 rs2416804 hCV30830319 rs7037673 0.51 0.321177244 0.4992 hCV16234795 rs2416804 hCV30830325 rs10818494 0.51 0.321177244 0.4528 hCV16234795 rs2416804 hCV30830340 rs10760134 0.51 0.321177244 0.4257 hCV16234795 rs2416804 hCV30830341 rs7040033 0.51 0.321177244 0.4257 hCV16234795 rs2416804 hCV30830415 rs7855998 0.51 0.321177244 0.3423 hCV16234795 rs2416804 hCV30830419 rs10985140 0.51 0.321177244 0.6604 hCV16234795 rs2416804 hCV30830427 rs10760142 0.51 0.321177244 0.3423 hCV16234795 rs2416804 hCV30830474 rs10739590 0.51 0.321177244 0.5503 hCV16234795 rs2416804 hCV30830638 rs10985073 0.51 0.321177244 0.9353 hCV16234795 rs2416804 hCV30830725 rs7864019 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV30830832 rs10733648 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV30830909 rs11794516 0.51 0.321177244 0.9353 hCV16234795 rs2416804 hCV7577254 rs942152 0.51 0.321177244 0.4043 hCV16234795 rs2416804 hCV7577317 rs1323472 0.51 0.321177244 0.6889 hCV16234795 rs2416804 hCV7577331 rs1468673 0.51 0.321177244 0.6889 hCV16234795 rs2416804 hCV7577337 rs993247 0.51 0.321177244 0.3592 hCV16234795 rs2416804 hCV7577344 rs876445 0.51 0.321177244 0.6341 hCV16234795 rs2416804 hCV782875 rs746182 0.51 0.321177244 0.476 hCV16234795 rs2416804 hCV8780517 rs1056567 0.51 0.321177244 0.3234 hCV1632190 rs10760146 hCV11720383 rs1951784 0.51 0.849855381 1 hCV1632190 rs10760146 hCV11720402 rs17611 0.51 0.849855381 0.9293 hCV1632190 rs10760146 hCV15751718 rs2296078 0.51 0.849855381 0.9649 hCV1632190 rs10760146 hCV15755658 rs2300934 0.51 0.849855381 0.8947 hCV1632190 rs10760146 hCV16234785 rs2416811 0.51 0.849855381 0.9293 hCV1632190 rs10760146 hCV2359571 rs25681 0.51 0.849855381 0.9293 hCV1632190 rs10760146 hCV25968825 rs10818504 0.51 0.849855381 1 hCV1632190 rs10760146 hCV26144282 rs10818499 0.51 0.849855381 0.9293 hCV1632190 rs10760146 hCV26144291 rs4570235 0.51 0.849855381 0.9293 hCV1632190 rs10760146 hCV26144296 rs10760143 0.51 0.849855381 1 hCV1632190 rs10760146 hCV27476319 rs3747843 0.51 0.849855381 0.9649 hCV1632190 rs10760146 hCV2783711 rs10733650 0.51 0.849855381 0.9293 hCV1632190 rs10760146 hCV29005933 rs7042135 0.51 0.849855381 0.8947 hCV1632190 rs10760146 hCV29005936 rs6478498 0.51 0.849855381 0.8947 hCV1632190 rs10760146 hCV29734592 rs10435889 0.51 0.849855381 0.9272 hCV1632190 rs10760146 hCV29824827 rs9657673 0.51 0.849855381 1 hCV1632190 rs10760146 hCV30041036 rs10156476 0.51 0.849855381 1 hCV1632190 rs10760146 hCV30167357 rs7022941 0.51 0.849855381 1 hCV1632190 rs10760146 hCV3045797 rs7036541 0.51 0.849855381 1 hCV1632190 rs10760146 hCV3045800 rs3736855 0.51 0.849855381 1 hCV1632190 rs10760146 hCV3045804 rs2057467 0.51 0.849855381 0.9484 hCV1632190 rs10760146 hCV3045808 rs10818516 0.51 0.849855381 0.9294 hCV1632190 rs10760146 hCV3045810 rs2209076 0.51 0.849855381 0.9314 hCV1632190 rs10760146 hCV30830415 rs7855998 0.51 0.849855381 0.8947 hCV1632190 rs10760146 hCV30830427 rs10760142 0.51 0.849855381 0.8947 hCV1632190 rs10760146 hCV30830440 rs10760144 0.51 0.849855381 1 hCV1632190 rs10760146 hCV30830506 rs10760151 0.51 0.849855381 1 hCV1632190 rs10760146 hCV30830537 rs10818515 0.51 0.849855381 0.9646 hCV1632190 rs10760146 hCV30830539 rs10760153 0.51 0.849855381 0.9642 hCV1632190 rs10760146 hCV30830540 rs10760154 0.51 0.849855381 0.9649 hCV1632190 rs10760146 hCV30830541 rs10760155 0.51 0.849855381 0.9649 hCV1632190 rs10760146 hCV30830542 rs10760156 0.51 0.849855381 0.9628 hCV1632190 rs10760146 hCV7577235 rs1052508 0.51 0.849855381 0.9649 hCV1632190 rs10760146 hCV7577248 rs1359086 0.51 0.849855381 0.9314 hCV1632190 rs10760146 hCV7577249 rs1359085 0.51 0.849855381 0.9649 hCV1632190 rs10760146 hCV7577337 rs993247 0.51 0.849855381 0.9293 hCV1761888 rs1953126 hCV11266229 rs10435844 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV11266268 rs10760121 0.51 0.531539009 1 hCV1761888 rs1953126 hCV11720413 rs1930782 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV11720414 rs1930781 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV15849116 rs2900180 0.51 0.531539009 0.9622 hCV1761888 rs1953126 hCV15870898 rs2072438 0.51 0.531539009 0.6691 hCV1761888 rs1953126 hCV16124825 rs2109895 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV16175379 rs2239657 0.51 0.531539009 0.9341 hCV1761888 rs1953126 hCV16234795 rs2416804 0.51 0.531539009 0.6014 hCV1761888 rs1953126 hCV1761891 rs1930778 0.51 0.531539009 1 hCV1761888 rs1953126 hCV1761894 rs1609810 0.51 0.531539009 1 hCV1761888 rs1953126 hCV2359565 rs1014530 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV25751916 rs10985070 0.51 0.531539009 0.6691 hCV1761888 rs1953126 hCV2783582 rs10818482 0.51 0.531539009 0.6691 hCV1761888 rs1953126 hCV2783586 rs2270231 0.51 0.531539009 1 hCV1761888 rs1953126 hCV2783589 rs881375 0.51 0.531539009 1 hCV1761888 rs1953126 hCV2783590 rs6478486 0.51 0.531539009 1 hCV1761888 rs1953126 hCV2783591 rs1468671 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783593 rs1548783 0.51 0.531539009 0.9661 hCV1761888 rs1953126 hCV2783597 rs1860824 0.51 0.531539009 0.965 hCV1761888 rs1953126 hCV2783599 rs7046108 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783604 rs10760126 0.51 0.531539009 0.6526 hCV1761888 rs1953126 hCV2783607 rs9886724 0.51 0.531539009 0.6785 hCV1761888 rs1953126 hCV2783608 rs4836834 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV2783609 rs2241003 0.51 0.531539009 0.9321 hCV1761888 rs1953126 hCV2783611 rs10435843 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783618 rs2239658 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783620 rs7021880 0.51 0.531539009 0.8974 hCV1761888 rs1953126 hCV2783621 rs2416805 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783622 rs758959 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783625 rs10118357 0.51 0.531539009 0.6295 hCV1761888 rs1953126 hCV2783630 rs2269060 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV2783633 rs7021049 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV2783634 rs1014529 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783635 rs1930780 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783638 rs3761846 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV2783640 rs3761847 0.51 0.531539009 0.6014 hCV1761888 rs1953126 hCV2783641 rs2416806 0.51 0.531539009 1 hCV1761888 rs1953126 hCV2783647 rs10739580 0.51 0.531539009 0.9666 hCV1761888 rs1953126 hCV2783650 rs10760129 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV2783653 rs10760130 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV2783655 rs10818488 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV2783656 rs4837804 0.51 0.531539009 0.8593 hCV1761888 rs1953126 hCV2783659 rs7039505 0.51 0.531539009 0.9615 hCV1761888 rs1953126 hCV29005976 rs7037195 0.51 0.531539009 0.6344 hCV1761888 rs1953126 hCV29005978 rs7021206 0.51 0.531539009 0.9651 hCV1761888 rs1953126 hCV29006006 rs7034390 0.51 0.531539009 1 hCV1761888 rs1953126 hCV30059070 rs10156413 0.51 0.531539009 0.5621 hCV1761888 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hCV1761894 rs1609810 hCV16124825 rs2109895 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV16175379 rs2239657 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV16180474 rs2273988 0.51 0.449770851 0.4757 hCV1761894 rs1609810 hCV16234795 rs2416804 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV16234838 rs2416819 0.51 0.449770851 0.5389 hCV1761894 rs1609810 hCV16234840 rs2416817 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV1632195 rs1998505 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV1632205 rs10818509 0.51 0.449770851 0.5059 hCV1761894 rs1609810 hCV1761888 rs1953126 0.51 0.449770851 1 hCV1761894 rs1609810 hCV1761891 rs1930778 0.51 0.449770851 1 hCV1761894 rs1609810 hCV2359565 rs1014530 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV25472748 rs10760138 0.51 0.449770851 0.4707 hCV1761894 rs1609810 hCV25613469 rs10760157 0.51 0.449770851 0.5389 hCV1761894 rs1609810 hCV25746749 rs7023214 0.51 0.449770851 0.5059 hCV1761894 rs1609810 hCV25751916 rs10985070 0.51 0.449770851 0.6485 hCV1761894 rs1609810 hCV25771057 rs10760150 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV25969661 rs10818503 0.51 0.449770851 0.5059 hCV1761894 rs1609810 hCV26144328 rs4836841 0.51 0.449770851 0.4757 hCV1761894 rs1609810 hCV2783582 rs10818482 0.51 0.449770851 0.6485 hCV1761894 rs1609810 hCV2783586 rs2270231 0.51 0.449770851 1 hCV1761894 rs1609810 hCV2783589 rs881375 0.51 0.449770851 1 hCV1761894 rs1609810 hCV2783590 rs6478486 0.51 0.449770851 1 hCV1761894 rs1609810 hCV2783591 rs1468671 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783593 rs1548783 0.51 0.449770851 0.9603 hCV1761894 rs1609810 hCV2783597 rs1860824 0.51 0.449770851 0.9588 hCV1761894 rs1609810 hCV2783599 rs7046108 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783604 rs10760126 0.51 0.449770851 0.6271 hCV1761894 rs1609810 hCV2783607 rs9886724 0.51 0.449770851 0.6581 hCV1761894 rs1609810 hCV2783608 rs4836834 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV2783609 rs2241003 0.51 0.449770851 0.9205 hCV1761894 rs1609810 hCV2783611 rs10435843 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783618 rs2239658 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783620 rs7021880 0.51 0.449770851 0.8797 hCV1761894 rs1609810 hCV2783621 rs2416805 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783622 rs758959 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783625 rs10118357 0.51 0.449770851 0.6003 hCV1761894 rs1609810 hCV2783630 rs2269060 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV2783633 rs7021049 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV2783634 rs1014529 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783635 rs1930780 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783638 rs3761846 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV2783640 rs3761847 0.51 0.449770851 0.5676 hCV1761894 rs1609810 hCV2783641 rs2416806 0.51 0.449770851 1 hCV1761894 rs1609810 hCV2783647 rs10739580 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV2783650 rs10760129 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV2783653 rs10760130 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV2783655 rs10818488 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV2783656 rs4837804 0.51 0.449770851 0.8728 hCV1761894 rs1609810 hCV2783659 rs7039505 0.51 0.449770851 0.9563 hCV1761894 rs1609810 hCV27912350 rs4837808 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV27912351 rs4837809 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV29005922 rs7033790 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV29005923 rs6478494 0.51 0.449770851 0.4707 hCV1761894 rs1609810 hCV29005924 rs7031128 0.51 0.449770851 0.5015 hCV1761894 rs1609810 hCV29005931 rs6478496 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV29005938 rs7856420 0.51 0.449770851 0.5059 hCV1761894 rs1609810 hCV29005976 rs7037195 0.51 0.449770851 0.6068 hCV1761894 rs1609810 hCV29005978 rs7021206 0.51 0.449770851 0.9588 hCV1761894 rs1609810 hCV29006006 rs7034390 0.51 0.449770851 1 hCV1761894 rs1609810 hCV30059070 rs10156413 0.51 0.449770851 0.6789 hCV1761894 rs1609810 hCV30293181 rs10081760 0.51 0.449770851 0.5042 hCV1761894 rs1609810 hCV3045792 rs6478499 0.51 0.449770851 0.5955 hCV1761894 rs1609810 hCV3045801 rs2057465 0.51 0.449770851 0.5261 hCV1761894 rs1609810 hCV3045802 rs2057466 0.51 0.449770851 0.4757 hCV1761894 rs1609810 hCV3045803 rs2146836 0.51 0.449770851 0.4757 hCV1761894 rs1609810 hCV30527383 rs9644911 0.51 0.449770851 0.4667 hCV1761894 rs1609810 hCV30563728 rs10156396 0.51 0.449770851 0.4753 hCV1761894 rs1609810 hCV30563729 rs9299273 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV30830342 rs7040319 0.51 0.449770851 0.4529 hCV1761894 rs1609810 hCV30830395 rs10985132 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV30830397 rs10760139 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV30830406 rs7040603 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV30830407 rs10739585 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV30830414 rs7871371 0.51 0.449770851 0.4949 hCV1761894 rs1609810 hCV30830417 rs7029523 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV30830435 rs10739586 0.51 0.449770851 0.5059 hCV1761894 rs1609810 hCV30830458 rs10733651 0.51 0.449770851 0.5059 hCV1761894 rs1609810 hCV30830468 rs10818507 0.51 0.449770851 0.5876 hCV1761894 rs1609810 hCV30830473 rs7036649 0.51 0.449770851 0.5901 hCV1761894 rs1609810 hCV30830475 rs10733652 0.51 0.449770851 0.5508 hCV1761894 rs1609810 hCV30830484 rs10818508 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV30830486 rs10760149 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV30830503 rs4837811 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV30830512 rs10818512 0.51 0.449770851 0.5389 hCV1761894 rs1609810 hCV30830521 rs10818513 0.51 0.449770851 0.5389 hCV1761894 rs1609810 hCV30830536 rs7047038 0.51 0.449770851 0.5389 hCV1761894 rs1609810 hCV30830538 rs10760152 0.51 0.449770851 0.4679 hCV1761894 rs1609810 hCV30830638 rs10985073 0.51 0.449770851 0.6485 hCV1761894 rs1609810 hCV30830725 rs7864019 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV30830832 rs10733648 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV30830909 rs11794516 0.51 0.449770851 0.6485 hCV1761894 rs1609810 hCV7577250 rs942153 0.51 0.449770851 0.5389 hCV1761894 rs1609810 hCV7577271 rs1535655 0.51 0.449770851 0.5389 hCV1761894 rs1609810 hCV7577286 rs1407912 0.51 0.449770851 0.5059 hCV1761894 rs1609810 hCV7577287 rs1323478 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV7577296 rs1407910 0.51 0.449770851 0.5717 hCV1761894 rs1609810 hCV7577311 rs1323473 0.51 0.449770851 0.4864 hCV1761894 rs1609810 hCV7577328 rs1323476 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV7577332 rs1468672 0.51 0.449770851 0.4793 hCV1761894 rs1609810 hCV7577344 rs876445 0.51 0.449770851 0.9609 hCV1761894 rs1609810 hCV782872 rs758958 0.51 0.449770851 0.4793 hCV1917481 rs10760112 hCV11297574 rs10760113 0.51 0.449378359 1 hCV1917481 rs10760112 hCV1452630 rs10818476 0.51 0.449378359 0.4938 hCV1917481 rs10760112 hCV1452651 rs3793638 0.51 0.449378359 0.5136 hCV1917481 rs10760112 hCV1452652 rs1060817 0.51 0.449378359 0.5136 hCV1917481 rs10760112 hCV1452665 rs4837796 0.51 0.449378359 0.4938 hCV1917481 rs10760112 hCV15849071 rs2900177 0.51 0.449378359 0.9558 hCV1917481 rs10760112 hCV1917479 rs10984994 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV1917497 rs10491784 0.51 0.449378359 1 hCV1917481 rs10760112 hCV1917498 rs920745 0.51 0.449378359 1 hCV1917481 rs10760112 hCV1917499 rs1867254 0.51 0.449378359 1 hCV1917481 rs10760112 hCV1917500 rs4837789 0.51 0.449378359 1 hCV1917481 rs10760112 hCV1917502 rs10984974 0.51 0.449378359 1 hCV1917481 rs10760112 hCV1917505 rs10760110 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV1917506 rs10984972 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV22272588 rs10760117 0.51 0.449378359 0.4938 hCV1917481 rs10760112 hCV25758615 rs7849566 0.51 0.449378359 1 hCV1917481 rs10760112 hCV26144235 rs1886337 0.51 0.449378359 1 hCV1917481 rs10760112 hCV26144244 rs4837792 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV26144245 rs4837793 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV26144246 rs4836830 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV27912345 rs4142158 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV29005915 rs7044106 0.51 0.449378359 0.7043 hCV1917481 rs10760112 hCV30419540 rs10491783 0.51 0.449378359 1 hCV1917481 rs10760112 hCV30829523 rs12343516 0.51 0.449378359 0.5136 hCV1917481 rs10760112 hCV30830175 rs10739569 0.51 0.449378359 0.7841 hCV1917481 rs10760112 hCV30830228 rs7024046 0.51 0.449378359 1 hCV1917481 rs10760112 hCV30830259 rs7044226 0.51 0.449378359 1 hCV1917481 rs10760112 hCV30830283 rs10818474 0.51 0.449378359 0.6426 hCV1917481 rs10760112 hCV30830295 rs7033339 0.51 0.449378359 0.79 hCV1917481 rs10760112 hCV3121925 rs4836831 0.51 0.449378359 0.9621 hCV1917481 rs10760112 hCV3121928 rs10985009 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121936 rs735110 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121937 rs735109 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121938 rs747819 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121944 rs2416799 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121945 rs4617229 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121960 rs966397 0.51 0.449378359 1 hCV1917481 rs10760112 hCV3121961 rs966396 0.51 0.449378359 1 hCV1917481 rs10760112 hCV3121962 rs4837790 0.51 0.449378359 1 hCV1917481 rs10760112 hCV3121966 rs1158553 0.51 0.449378359 1 hCV1917481 rs10760112 hCV3121967 rs1158554 0.51 0.449378359 1 hCV1917481 rs10760112 hCV3121972 rs7357638 0.51 0.449378359 1 hCV1917481 rs10760112 hCV3121975 rs1981021 0.51 0.449378359 1 hCV1917481 rs10760112 hCV3121979 rs3903886 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121981 rs10739570 0.51 0.449378359 0.9632 hCV1917481 rs10760112 hCV3121982 rs7861679 0.51 0.449378359 0.8916 hCV1917481 rs10760112 hCV3121983 rs2416760 0.51 0.449378359 0.8916 hCV1917481 rs10760112 hCV3121984 rs991121 0.51 0.449378359 0.8904 hCV1917481 rs10760112 hCV3121985 rs959558 0.51 0.449378359 0.8916 hCV1917481 rs10760112 hCV3121987 rs10616 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rs10760117 hCV26144246 rs4836830 0.51 0.29326589 0.4997 hCV22272588 rs10760117 hCV2783582 rs10818482 0.51 0.29326589 0.3756 hCV22272588 rs10760117 hCV2783586 rs2270231 0.51 0.29326589 0.3842 hCV22272588 rs10760117 hCV2783589 rs881375 0.51 0.29326589 0.3842 hCV22272588 rs10760117 hCV2783590 rs6478486 0.51 0.29326589 0.3842 hCV22272588 rs10760117 hCV2783591 rs1468671 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783593 rs1548783 0.51 0.29326589 0.3754 hCV22272588 rs10760117 hCV2783597 rs1860824 0.51 0.29326589 0.3376 hCV22272588 rs10760117 hCV2783599 rs7046108 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783604 rs10760126 0.51 0.29326589 0.362 hCV22272588 rs10760117 hCV2783607 rs9886724 0.51 0.29326589 0.3695 hCV22272588 rs10760117 hCV2783608 rs4836834 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV2783609 rs2241003 0.51 0.29326589 0.406 hCV22272588 rs10760117 hCV2783611 rs10435843 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783618 rs2239658 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783620 rs7021880 0.51 0.29326589 0.3276 hCV22272588 rs10760117 hCV2783621 rs2416805 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783622 rs758959 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783625 rs10118357 0.51 0.29326589 0.3662 hCV22272588 rs10760117 hCV2783630 rs2269060 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV2783633 rs7021049 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV2783634 rs1014529 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783635 rs1930780 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783638 rs3761846 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV2783640 rs3761847 0.51 0.29326589 0.3275 hCV22272588 rs10760117 hCV2783641 rs2416806 0.51 0.29326589 0.3646 hCV22272588 rs10760117 hCV2783647 rs10739580 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV2783650 rs10760129 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV2783653 rs10760130 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV2783655 rs10818488 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV2783656 rs4837804 0.51 0.29326589 0.3051 hCV22272588 rs10760117 hCV2783659 rs7039505 0.51 0.29326589 0.3838 hCV22272588 rs10760117 hCV27912345 rs4142158 0.51 0.29326589 0.4475 hCV22272588 rs10760117 hCV29005915 rs7044106 0.51 0.29326589 0.3396 hCV22272588 rs10760117 hCV29005976 rs7037195 0.51 0.29326589 0.3495 hCV22272588 rs10760117 hCV29005978 rs7021206 0.51 0.29326589 0.3583 hCV22272588 rs10760117 hCV29006006 rs7034390 0.51 0.29326589 0.3842 hCV22272588 rs10760117 hCV30419540 rs10491783 0.51 0.29326589 0.4666 hCV22272588 rs10760117 hCV30829523 rs12343516 0.51 0.29326589 0.9672 hCV22272588 rs10760117 hCV30830175 rs10739569 0.51 0.29326589 0.3535 hCV22272588 rs10760117 hCV30830228 rs7024046 0.51 0.29326589 0.4666 hCV22272588 rs10760117 hCV30830259 rs7044226 0.51 0.29326589 0.5063 hCV22272588 rs10760117 hCV30830283 rs10818474 0.51 0.29326589 0.3723 hCV22272588 rs10760117 hCV30830295 rs7033339 0.51 0.29326589 0.4533 hCV22272588 rs10760117 hCV30830638 rs10985073 0.51 0.29326589 0.3756 hCV22272588 rs10760117 hCV30830725 rs7864019 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV30830832 rs10733648 0.51 0.29326589 0.3629 hCV22272588 rs10760117 hCV30830909 rs11794516 0.51 0.29326589 0.3756 hCV22272588 rs10760117 hCV3121925 rs4836831 0.51 0.29326589 0.4882 hCV22272588 rs10760117 hCV3121928 rs10985009 0.51 0.29326589 0.4997 hCV22272588 rs10760117 hCV3121936 rs735110 0.51 0.29326589 0.4997 hCV22272588 rs10760117 hCV3121937 rs735109 0.51 0.29326589 0.4997 hCV22272588 rs10760117 hCV3121938 rs747819 0.51 0.29326589 0.4997 hCV22272588 rs10760117 hCV3121944 rs2416799 0.51 0.29326589 0.4997 hCV22272588 rs10760117 hCV3121945 rs4617229 0.51 0.29326589 0.4997 hCV22272588 rs10760117 hCV3121960 rs966397 0.51 0.29326589 0.4666 hCV22272588 rs10760117 hCV3121961 rs966396 0.51 0.29326589 0.4666 hCV22272588 rs10760117 hCV3121962 rs4837790 0.51 0.29326589 0.4666 hCV22272588 rs10760117 hCV3121966 rs1158553 0.51 0.29326589 0.4666 hCV22272588 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rs10760117 hCV7577377 rs1359328 0.51 0.29326589 0.2949 hCV22272588 rs10760117 hCV8780517 rs1056567 0.51 0.29326589 0.4886 hCV22272588 rs10760117 hCV8780961 rs914842 0.51 0.29326589 0.3563 hCV22272588 rs10760117 hCV8780962 rs1837 0.51 0.29326589 0.4622 hCV25612709 rs7026635 hCV1761881 rs3933326 0.51 0.604602471 0.7321 hCV25612709 rs7026635 hCV25757804 rs4836833 0.51 0.604602471 0.7608 hCV25612709 rs7026635 hCV26144018 rs10739575 0.51 0.604602471 0.6374 hCV25612709 rs7026635 hCV8780517 rs1056567 0.51 0.604602471 0.7608 hCV25612709 rs7026635 hCV8780961 rs914842 0.51 0.604602471 0.6667 hCV25612709 rs7026635 hCV8780962 rs1837 0.51 0.604602471 0.8902 hCV25751916 rs10985070 hCV11266229 rs10435844 0.51 0.348238045 0.6467 hCV25751916 rs10985070 hCV11266268 rs10760121 0.51 0.348238045 0.6691 hCV25751916 rs10985070 hCV11720351 rs1885995 0.51 0.348238045 0.4963 hCV25751916 rs10985070 hCV11720413 rs1930782 0.51 0.348238045 0.9671 hCV25751916 rs10985070 hCV11720414 rs1930781 0.51 0.348238045 0.6467 hCV25751916 rs10985070 hCV1452630 rs10818476 0.51 0.348238045 0.3756 hCV25751916 rs10985070 hCV1452651 rs3793638 0.51 0.348238045 0.3542 hCV25751916 rs10985070 hCV1452652 rs1060817 0.51 0.348238045 0.3542 hCV25751916 rs10985070 hCV1452665 rs4837796 0.51 0.348238045 0.3756 hCV25751916 rs10985070 hCV15751717 rs2296077 0.51 0.348238045 0.4374 hCV25751916 rs10985070 hCV15751719 rs2146838 0.51 0.348238045 0.4963 hCV25751916 rs10985070 hCV15757738 rs2302498 0.51 0.348238045 0.4505 hCV25751916 rs10985070 hCV15849116 rs2900180 0.51 0.348238045 0.6342 hCV25751916 rs10985070 hCV15870898 rs2072438 0.51 0.348238045 1 hCV25751916 rs10985070 hCV16124825 rs2109895 0.51 0.348238045 0.6467 hCV25751916 rs10985070 hCV16175379 rs2239657 0.51 0.348238045 0.625 hCV25751916 rs10985070 hCV16234795 rs2416804 0.51 0.348238045 0.9353 hCV25751916 rs10985070 hCV1761881 rs3933326 0.51 0.348238045 0.3563 hCV25751916 rs10985070 hCV1761888 rs1953126 0.51 0.348238045 0.6691 hCV25751916 rs10985070 hCV1761891 rs1930778 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0.90039199 1 hCV25763321 rs3747841 hCV30830913 rs10818489 0.51 0.90039199 1 hCV25763321 rs3747841 hCV30830915 rs10985105 0.51 0.90039199 1 hCV25763321 rs3747841 hCV30830938 rs12235400 0.51 0.90039199 1 hCV2783582 rs10818482 hCV11266229 rs10435844 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV11266268 rs10760121 0.51 0.33772028 0.6691 hCV2783582 rs10818482 hCV11720351 rs1885995 0.51 0.33772028 0.4963 hCV2783582 rs10818482 hCV11720402 rs17611 0.51 0.33772028 0.347 hCV2783582 rs10818482 hCV11720413 rs1930782 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV11720414 rs1930781 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV1452630 rs10818476 0.51 0.33772028 0.3756 hCV2783582 rs10818482 hCV1452651 rs3793638 0.51 0.33772028 0.3542 hCV2783582 rs10818482 hCV1452652 rs1060817 0.51 0.33772028 0.3542 hCV2783582 rs10818482 hCV1452665 rs4837796 0.51 0.33772028 0.3756 hCV2783582 rs10818482 hCV15751717 rs2296077 0.51 0.33772028 0.4374 hCV2783582 rs10818482 hCV15751719 rs2146838 0.51 0.33772028 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hCV2783582 rs10818482 hCV25757804 rs4836833 0.51 0.33772028 0.3396 hCV2783582 rs10818482 hCV26144282 rs10818499 0.51 0.33772028 0.347 hCV2783582 rs10818482 hCV26144291 rs4570235 0.51 0.33772028 0.347 hCV2783582 rs10818482 hCV26144307 rs1016468 0.51 0.33772028 0.4963 hCV2783582 rs10818482 hCV26144332 rs4837813 0.51 0.33772028 0.4761 hCV2783582 rs10818482 hCV2783586 rs2270231 0.51 0.33772028 0.6691 hCV2783582 rs10818482 hCV2783589 rs881375 0.51 0.33772028 0.6691 hCV2783582 rs10818482 hCV2783590 rs6478486 0.51 0.33772028 0.6691 hCV2783582 rs10818482 hCV2783591 rs1468671 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783593 rs1548783 0.51 0.33772028 0.6423 hCV2783582 rs10818482 hCV2783597 rs1860824 0.51 0.33772028 0.6357 hCV2783582 rs10818482 hCV2783599 rs7046108 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783604 rs10760126 0.51 0.33772028 0.9666 hCV2783582 rs10818482 hCV2783607 rs9886724 0.51 0.33772028 1 hCV2783582 rs10818482 hCV2783608 rs4836834 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV2783609 rs2241003 0.51 0.33772028 0.7074 hCV2783582 rs10818482 hCV2783611 rs10435843 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783618 rs2239658 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783620 rs7021880 0.51 0.33772028 0.5878 hCV2783582 rs10818482 hCV2783621 rs2416805 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783622 rs758959 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783625 rs10118357 0.51 0.33772028 0.9665 hCV2783582 rs10818482 hCV2783630 rs2269060 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV2783633 rs7021049 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV2783634 rs1014529 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783635 rs1930780 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783638 rs3761846 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV2783640 rs3761847 0.51 0.33772028 0.9353 hCV2783582 rs10818482 hCV2783641 rs2416806 0.51 0.33772028 0.6594 hCV2783582 rs10818482 hCV2783647 rs10739580 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV2783650 rs10760129 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV2783653 rs10760130 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV2783655 rs10818488 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV2783656 rs4837804 0.51 0.33772028 0.7472 hCV2783582 rs10818482 hCV2783659 rs7039505 0.51 0.33772028 0.6319 hCV2783582 rs10818482 hCV2783711 rs10733650 0.51 0.33772028 0.3903 hCV2783582 rs10818482 hCV2783718 rs10818500 0.51 0.33772028 0.6972 hCV2783582 rs10818482 hCV29005955 rs7036980 0.51 0.33772028 0.4304 hCV2783582 rs10818482 hCV29005976 rs7037195 0.51 0.33772028 0.9671 hCV2783582 rs10818482 hCV29005978 rs7021206 0.51 0.33772028 0.6788 hCV2783582 rs10818482 hCV29006006 rs7034390 0.51 0.33772028 0.6691 hCV2783582 rs10818482 hCV29879049 rs9792437 0.51 0.33772028 0.4711 hCV2783582 rs10818482 hCV3045812 rs7030849 0.51 0.33772028 0.4711 hCV2783582 rs10818482 hCV30829523 rs12343516 0.51 0.33772028 0.3542 hCV2783582 rs10818482 hCV30830319 rs7037673 0.51 0.33772028 0.5359 hCV2783582 rs10818482 hCV30830325 rs10818494 0.51 0.33772028 0.4346 hCV2783582 rs10818482 hCV30830340 rs10760134 0.51 0.33772028 0.4135 hCV2783582 rs10818482 hCV30830341 rs7040033 0.51 0.33772028 0.4135 hCV2783582 rs10818482 hCV30830419 rs10985140 0.51 0.33772028 0.6598 hCV2783582 rs10818482 hCV30830474 rs10739590 0.51 0.33772028 0.5521 hCV2783582 rs10818482 hCV30830638 rs10985073 0.51 0.33772028 1 hCV2783582 rs10818482 hCV30830725 rs7864019 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV30830832 rs10733648 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV30830909 rs11794516 0.51 0.33772028 1 hCV2783582 rs10818482 hCV7577254 rs942152 0.51 0.33772028 0.4017 hCV2783582 rs10818482 hCV7577317 rs1323472 0.51 0.33772028 0.6896 hCV2783582 rs10818482 hCV7577331 rs1468673 0.51 0.33772028 0.6896 hCV2783582 rs10818482 hCV7577337 rs993247 0.51 0.33772028 0.347 hCV2783582 rs10818482 hCV7577344 rs876445 0.51 0.33772028 0.6467 hCV2783582 rs10818482 hCV782875 rs746182 0.51 0.33772028 0.4761 hCV2783582 rs10818482 hCV8780517 rs1056567 0.51 0.33772028 0.3396 hCV2783586 rs2270231 hCV11266229 rs10435844 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV11266268 rs10760121 0.51 0.467936232 1 hCV2783586 rs2270231 hCV11720350 rs2057469 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV11720413 rs1930782 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV11720414 rs1930781 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV15849105 rs2900185 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV15849116 rs2900180 0.51 0.467936232 0.9622 hCV2783586 rs2270231 hCV15870898 rs2072438 0.51 0.467936232 0.6691 hCV2783586 rs2270231 hCV16124825 rs2109895 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV16175379 rs2239657 0.51 0.467936232 0.9341 hCV2783586 rs2270231 hCV16234795 rs2416804 0.51 0.467936232 0.6014 hCV2783586 rs2270231 hCV16234838 rs2416819 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV16234840 rs2416817 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV1632195 rs1998505 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV1761888 rs1953126 0.51 0.467936232 1 hCV2783586 rs2270231 hCV1761891 rs1930778 0.51 0.467936232 1 hCV2783586 rs2270231 hCV1761894 rs1609810 0.51 0.467936232 1 hCV2783586 rs2270231 hCV2359565 rs1014530 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV25613469 rs10760157 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV25751916 rs10985070 0.51 0.467936232 0.6691 hCV2783586 rs2270231 hCV25771057 rs10760150 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV2783582 rs10818482 0.51 0.467936232 0.6691 hCV2783586 rs2270231 hCV2783589 rs881375 0.51 0.467936232 1 hCV2783586 rs2270231 hCV2783590 rs6478486 0.51 0.467936232 1 hCV2783586 rs2270231 hCV2783591 rs1468671 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783593 rs1548783 0.51 0.467936232 0.9661 hCV2783586 rs2270231 hCV2783597 rs1860824 0.51 0.467936232 0.965 hCV2783586 rs2270231 hCV2783599 rs7046108 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783604 rs10760126 0.51 0.467936232 0.6526 hCV2783586 rs2270231 hCV2783607 rs9886724 0.51 0.467936232 0.6785 hCV2783586 rs2270231 hCV2783608 rs4836834 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV2783609 rs2241003 0.51 0.467936232 0.9321 hCV2783586 rs2270231 hCV2783611 rs10435843 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783618 rs2239658 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783620 rs7021880 0.51 0.467936232 0.8974 hCV2783586 rs2270231 hCV2783621 rs2416805 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783622 rs758959 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783625 rs10118357 0.51 0.467936232 0.6295 hCV2783586 rs2270231 hCV2783630 rs2269060 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV2783633 rs7021049 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV2783634 rs1014529 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783635 rs1930780 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783638 rs3761846 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV2783640 rs3761847 0.51 0.467936232 0.6014 hCV2783586 rs2270231 hCV2783641 rs2416806 0.51 0.467936232 1 hCV2783586 rs2270231 hCV2783647 rs10739580 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV2783650 rs10760129 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV2783653 rs10760130 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV2783655 rs10818488 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV2783656 rs4837804 0.51 0.467936232 0.8593 hCV2783586 rs2270231 hCV2783659 rs7039505 0.51 0.467936232 0.9615 hCV2783586 rs2270231 hCV27912350 rs4837808 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV27912351 rs4837809 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV29005924 rs7031128 0.51 0.467936232 0.4729 hCV2783586 rs2270231 hCV29005976 rs7037195 0.51 0.467936232 0.6344 hCV2783586 rs2270231 hCV29005978 rs7021206 0.51 0.467936232 0.9651 hCV2783586 rs2270231 hCV29006006 rs7034390 0.51 0.467936232 1 hCV2783586 rs2270231 hCV30059070 rs10156413 0.51 0.467936232 0.5621 hCV2783586 rs2270231 hCV3045792 rs6478499 0.51 0.467936232 0.5164 hCV2783586 rs2270231 hCV30563729 rs9299273 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV30830468 rs10818507 0.51 0.467936232 0.4819 hCV2783586 rs2270231 hCV30830473 rs7036649 0.51 0.467936232 0.5014 hCV2783586 rs2270231 hCV30830484 rs10818508 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV30830486 rs10760149 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV30830503 rs4837811 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV30830512 rs10818512 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV30830521 rs10818513 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV30830536 rs7047038 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV30830638 rs10985073 0.51 0.467936232 0.6691 hCV2783586 rs2270231 hCV30830725 rs7864019 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV30830832 rs10733648 0.51 0.467936232 0.9666 hCV2783586 rs2270231 hCV30830909 rs11794516 0.51 0.467936232 0.6691 hCV2783586 rs2270231 hCV7577250 rs942153 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV7577271 rs1535655 0.51 0.467936232 0.4734 hCV2783586 rs2270231 hCV7577287 rs1323478 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV7577296 rs1407910 0.51 0.467936232 0.4989 hCV2783586 rs2270231 hCV7577344 rs876445 0.51 0.467936232 0.9666 hCV2783589 rs881375 hCV11266229 rs10435844 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV11266268 rs10760121 0.51 0.499966299 1 hCV2783589 rs881375 hCV11720413 rs1930782 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV11720414 rs1930781 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV15849116 rs2900180 0.51 0.499966299 0.9622 hCV2783589 rs881375 hCV15870898 rs2072438 0.51 0.499966299 0.6691 hCV2783589 rs881375 hCV16124825 rs2109895 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV16175379 rs2239657 0.51 0.499966299 0.9341 hCV2783589 rs881375 hCV16234795 rs2416804 0.51 0.499966299 0.6014 hCV2783589 rs881375 hCV1761888 rs1953126 0.51 0.499966299 1 hCV2783589 rs881375 hCV1761891 rs1930778 0.51 0.499966299 1 hCV2783589 rs881375 hCV1761894 rs1609810 0.51 0.499966299 1 hCV2783589 rs881375 hCV2359565 rs1014530 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV25751916 rs10985070 0.51 0.499966299 0.6691 hCV2783589 rs881375 hCV2783582 rs10818482 0.51 0.499966299 0.6691 hCV2783589 rs881375 hCV2783586 rs2270231 0.51 0.499966299 1 hCV2783589 rs881375 hCV2783590 rs6478486 0.51 0.499966299 1 hCV2783589 rs881375 hCV2783591 rs1468671 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783593 rs1548783 0.51 0.499966299 0.9661 hCV2783589 rs881375 hCV2783597 rs1860824 0.51 0.499966299 0.965 hCV2783589 rs881375 hCV2783599 rs7046108 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783604 rs10760126 0.51 0.499966299 0.6526 hCV2783589 rs881375 hCV2783607 rs9886724 0.51 0.499966299 0.6785 hCV2783589 rs881375 hCV2783608 rs4836834 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV2783609 rs2241003 0.51 0.499966299 0.9321 hCV2783589 rs881375 hCV2783611 rs10435843 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783618 rs2239658 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783620 rs7021880 0.51 0.499966299 0.8974 hCV2783589 rs881375 hCV2783621 rs2416805 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783622 rs758959 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783625 rs10118357 0.51 0.499966299 0.6295 hCV2783589 rs881375 hCV2783630 rs2269060 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV2783633 rs7021049 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV2783634 rs1014529 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783635 rs1930780 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783638 rs3761846 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV2783640 rs3761847 0.51 0.499966299 0.6014 hCV2783589 rs881375 hCV2783641 rs2416806 0.51 0.499966299 1 hCV2783589 rs881375 hCV2783647 rs10739580 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV2783650 rs10760129 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV2783653 rs10760130 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV2783655 rs10818488 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV2783656 rs4837804 0.51 0.499966299 0.8593 hCV2783589 rs881375 hCV2783659 rs7039505 0.51 0.499966299 0.9615 hCV2783589 rs881375 hCV29005976 rs7037195 0.51 0.499966299 0.6344 hCV2783589 rs881375 hCV29005978 rs7021206 0.51 0.499966299 0.9651 hCV2783589 rs881375 hCV29006006 rs7034390 0.51 0.499966299 1 hCV2783589 rs881375 hCV30059070 rs10156413 0.51 0.499966299 0.5621 hCV2783589 rs881375 hCV3045792 rs6478499 0.51 0.499966299 0.5164 hCV2783589 rs881375 hCV30830473 rs7036649 0.51 0.499966299 0.5014 hCV2783589 rs881375 hCV30830638 rs10985073 0.51 0.499966299 0.6691 hCV2783589 rs881375 hCV30830725 rs7864019 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV30830832 rs10733648 0.51 0.499966299 0.9666 hCV2783589 rs881375 hCV30830909 rs11794516 0.51 0.499966299 0.6691 hCV2783589 rs881375 hCV7577344 rs876445 0.51 0.499966299 0.9666 hCV2783590 rs6478486 hCV11266229 rs10435844 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV11266268 rs10760121 0.51 0.400501157 1 hCV2783590 rs6478486 hCV11720350 rs2057469 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV11720386 rs1998506 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV11720394 rs1924081 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV11720413 rs1930782 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV11720414 rs1930781 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV15849105 rs2900185 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV15849116 rs2900180 0.51 0.400501157 0.9622 hCV2783590 rs6478486 hCV15870898 rs2072438 0.51 0.400501157 0.6691 hCV2783590 rs6478486 hCV16124825 rs2109895 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV16175379 rs2239657 0.51 0.400501157 0.9341 hCV2783590 rs6478486 hCV16180474 rs2273988 0.51 0.400501157 0.4011 hCV2783590 rs6478486 hCV16234795 rs2416804 0.51 0.400501157 0.6014 hCV2783590 rs6478486 hCV16234838 rs2416819 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV16234840 rs2416817 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV1632195 rs1998505 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV1632205 rs10818509 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV1761888 rs1953126 0.51 0.400501157 1 hCV2783590 rs6478486 hCV1761891 rs1930778 0.51 0.400501157 1 hCV2783590 rs6478486 hCV1761894 rs1609810 0.51 0.400501157 1 hCV2783590 rs6478486 hCV2359565 rs1014530 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV25472748 rs10760138 0.51 0.400501157 0.4328 hCV2783590 rs6478486 hCV25613469 rs10760157 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV25746749 rs7023214 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV25751916 rs10985070 0.51 0.400501157 0.6691 hCV2783590 rs6478486 hCV25771057 rs10760150 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV25969661 rs10818503 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV26144328 rs4836841 0.51 0.400501157 0.4011 hCV2783590 rs6478486 hCV2783582 rs10818482 0.51 0.400501157 0.6691 hCV2783590 rs6478486 hCV2783586 rs2270231 0.51 0.400501157 1 hCV2783590 rs6478486 hCV2783589 rs881375 0.51 0.400501157 1 hCV2783590 rs6478486 hCV2783591 rs1468671 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783593 rs1548783 0.51 0.400501157 0.9661 hCV2783590 rs6478486 hCV2783597 rs1860824 0.51 0.400501157 0.965 hCV2783590 rs6478486 hCV2783599 rs7046108 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783604 rs10760126 0.51 0.400501157 0.6526 hCV2783590 rs6478486 hCV2783607 rs9886724 0.51 0.400501157 0.6785 hCV2783590 rs6478486 hCV2783608 rs4836834 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV2783609 rs2241003 0.51 0.400501157 0.9321 hCV2783590 rs6478486 hCV2783611 rs10435843 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783618 rs2239658 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783620 rs7021880 0.51 0.400501157 0.8974 hCV2783590 rs6478486 hCV2783621 rs2416805 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783622 rs758959 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783625 rs10118357 0.51 0.400501157 0.6295 hCV2783590 rs6478486 hCV2783630 rs2269060 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV2783633 rs7021049 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV2783634 rs1014529 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783635 rs1930780 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783638 rs3761846 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV2783640 rs3761847 0.51 0.400501157 0.6014 hCV2783590 rs6478486 hCV2783641 rs2416806 0.51 0.400501157 1 hCV2783590 rs6478486 hCV2783647 rs10739580 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV2783650 rs10760129 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV2783653 rs10760130 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV2783655 rs10818488 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV2783656 rs4837804 0.51 0.400501157 0.8593 hCV2783590 rs6478486 hCV2783659 rs7039505 0.51 0.400501157 0.9615 hCV2783590 rs6478486 hCV27912350 rs4837808 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV27912351 rs4837809 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV29005922 rs7033790 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV29005923 rs6478494 0.51 0.400501157 0.4648 hCV2783590 rs6478486 hCV29005924 rs7031128 0.51 0.400501157 0.4729 hCV2783590 rs6478486 hCV29005931 rs6478496 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV29005938 rs7856420 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV29005976 rs7037195 0.51 0.400501157 0.6344 hCV2783590 rs6478486 hCV29005978 rs7021206 0.51 0.400501157 0.9651 hCV2783590 rs6478486 hCV29006006 rs7034390 0.51 0.400501157 1 hCV2783590 rs6478486 hCV30059070 rs10156413 0.51 0.400501157 0.5621 hCV2783590 rs6478486 hCV30293181 rs10081760 0.51 0.400501157 0.4218 hCV2783590 rs6478486 hCV3045792 rs6478499 0.51 0.400501157 0.5164 hCV2783590 rs6478486 hCV3045801 rs2057465 0.51 0.400501157 0.4611 hCV2783590 rs6478486 hCV3045802 rs2057466 0.51 0.400501157 0.4011 hCV2783590 rs6478486 hCV3045803 rs2146836 0.51 0.400501157 0.4011 hCV2783590 rs6478486 hCV30527383 rs9644911 0.51 0.400501157 0.4218 hCV2783590 rs6478486 hCV30563728 rs10156396 0.51 0.400501157 0.429 hCV2783590 rs6478486 hCV30563729 rs9299273 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV30830342 rs7040319 0.51 0.400501157 0.4044 hCV2783590 rs6478486 hCV30830395 rs10985132 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV30830397 rs10760139 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV30830406 rs7040603 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV30830407 rs10739585 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV30830414 rs7871371 0.51 0.400501157 0.4541 hCV2783590 rs6478486 hCV30830417 rs7029523 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV30830435 rs10739586 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV30830458 rs10733651 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV30830468 rs10818507 0.51 0.400501157 0.4819 hCV2783590 rs6478486 hCV30830473 rs7036649 0.51 0.400501157 0.5014 hCV2783590 rs6478486 hCV30830475 rs10733652 0.51 0.400501157 0.4539 hCV2783590 rs6478486 hCV30830484 rs10818508 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV30830486 rs10760149 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV30830503 rs4837811 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV30830512 rs10818512 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV30830521 rs10818513 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV30830536 rs7047038 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV30830538 rs10760152 0.51 0.400501157 0.4168 hCV2783590 rs6478486 hCV30830638 rs10985073 0.51 0.400501157 0.6691 hCV2783590 rs6478486 hCV30830725 rs7864019 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV30830832 rs10733648 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV30830909 rs11794516 0.51 0.400501157 0.6691 hCV2783590 rs6478486 hCV7577250 rs942153 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV7577271 rs1535655 0.51 0.400501157 0.4734 hCV2783590 rs6478486 hCV7577286 rs1407912 0.51 0.400501157 0.4237 hCV2783590 rs6478486 hCV7577287 rs1323478 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV7577296 rs1407910 0.51 0.400501157 0.4989 hCV2783590 rs6478486 hCV7577311 rs1323473 0.51 0.400501157 0.4466 hCV2783590 rs6478486 hCV7577317 rs1323472 0.51 0.400501157 0.404 hCV2783590 rs6478486 hCV7577328 rs1323476 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV7577331 rs1468673 0.51 0.400501157 0.404 hCV2783590 rs6478486 hCV7577332 rs1468672 0.51 0.400501157 0.4414 hCV2783590 rs6478486 hCV7577344 rs876445 0.51 0.400501157 0.9666 hCV2783590 rs6478486 hCV782872 rs758958 0.51 0.400501157 0.4414 hCV2783597 rs1860824 hCV11266229 rs10435844 0.51 0.424042897 1 hCV2783597 rs1860824 hCV11266268 rs10760121 0.51 0.424042897 0.965 hCV2783597 rs1860824 hCV11720350 rs2057469 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV11720413 rs1930782 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV11720414 rs1930781 0.51 0.424042897 1 hCV2783597 rs1860824 hCV15849105 rs2900185 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV15849116 rs2900180 0.51 0.424042897 1 hCV2783597 rs1860824 hCV15870898 rs2072438 0.51 0.424042897 0.6357 hCV2783597 rs1860824 hCV16124825 rs2109895 0.51 0.424042897 1 hCV2783597 rs1860824 hCV16175379 rs2239657 0.51 0.424042897 0.9647 hCV2783597 rs1860824 hCV16234795 rs2416804 0.51 0.424042897 0.6215 hCV2783597 rs1860824 hCV16234838 rs2416819 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV16234840 rs2416817 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV1632195 rs1998505 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV1761888 rs1953126 0.51 0.424042897 0.965 hCV2783597 rs1860824 hCV1761891 rs1930778 0.51 0.424042897 0.959 hCV2783597 rs1860824 hCV1761894 rs1609810 0.51 0.424042897 0.9588 hCV2783597 rs1860824 hCV2359565 rs1014530 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV25613469 rs10760157 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV25751916 rs10985070 0.51 0.424042897 0.6357 hCV2783597 rs1860824 hCV25771057 rs10760150 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV2783582 rs10818482 0.51 0.424042897 0.6357 hCV2783597 rs1860824 hCV2783586 rs2270231 0.51 0.424042897 0.965 hCV2783597 rs1860824 hCV2783589 rs881375 0.51 0.424042897 0.965 hCV2783597 rs1860824 hCV2783590 rs6478486 0.51 0.424042897 0.965 hCV2783597 rs1860824 hCV2783591 rs1468671 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783593 rs1548783 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783599 rs7046108 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783604 rs10760126 0.51 0.424042897 0.6773 hCV2783597 rs1860824 hCV2783607 rs9886724 0.51 0.424042897 0.6676 hCV2783597 rs1860824 hCV2783608 rs4836834 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV2783609 rs2241003 0.51 0.424042897 0.9289 hCV2783597 rs1860824 hCV2783611 rs10435843 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783618 rs2239658 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783620 rs7021880 0.51 0.424042897 0.9627 hCV2783597 rs1860824 hCV2783621 rs2416805 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783622 rs758959 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783625 rs10118357 0.51 0.424042897 0.6539 hCV2783597 rs1860824 hCV2783630 rs2269060 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV2783633 rs7021049 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV2783634 rs1014529 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783635 rs1930780 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783638 rs3761846 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV2783640 rs3761847 0.51 0.424042897 0.6215 hCV2783597 rs1860824 hCV2783641 rs2416806 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783647 rs10739580 0.51 0.424042897 1 hCV2783597 rs1860824 hCV2783650 rs10760129 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV2783653 rs10760130 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV2783655 rs10818488 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV2783656 rs4837804 0.51 0.424042897 0.8909 hCV2783597 rs1860824 hCV2783659 rs7039505 0.51 0.424042897 1 hCV2783597 rs1860824 hCV27912350 rs4837808 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV27912351 rs4837809 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV29005923 rs6478494 0.51 0.424042897 0.4396 hCV2783597 rs1860824 hCV29005924 rs7031128 0.51 0.424042897 0.4439 hCV2783597 rs1860824 hCV29005976 rs7037195 0.51 0.424042897 0.6581 hCV2783597 rs1860824 hCV29005978 rs7021206 0.51 0.424042897 1 hCV2783597 rs1860824 hCV29006006 rs7034390 0.51 0.424042897 0.965 hCV2783597 rs1860824 hCV30059070 rs10156413 0.51 0.424042897 0.5428 hCV2783597 rs1860824 hCV3045792 rs6478499 0.51 0.424042897 0.4923 hCV2783597 rs1860824 hCV3045801 rs2057465 0.51 0.424042897 0.4342 hCV2783597 rs1860824 hCV30563729 rs9299273 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV30830414 rs7871371 0.51 0.424042897 0.4332 hCV2783597 rs1860824 hCV30830468 rs10818507 0.51 0.424042897 0.4577 hCV2783597 rs1860824 hCV30830473 rs7036649 0.51 0.424042897 0.4725 hCV2783597 rs1860824 hCV30830475 rs10733652 0.51 0.424042897 0.4293 hCV2783597 rs1860824 hCV30830484 rs10818508 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV30830486 rs10760149 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV30830503 rs4837811 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV30830512 rs10818512 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV30830521 rs10818513 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV30830536 rs7047038 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV30830638 rs10985073 0.51 0.424042897 0.6357 hCV2783597 rs1860824 hCV30830725 rs7864019 0.51 0.424042897 1 hCV2783597 rs1860824 hCV30830832 rs10733648 0.51 0.424042897 1 hCV2783597 rs1860824 hCV30830909 rs11794516 0.51 0.424042897 0.6357 hCV2783597 rs1860824 hCV7577250 rs942153 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV7577271 rs1535655 0.51 0.424042897 0.4487 hCV2783597 rs1860824 hCV7577287 rs1323478 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV7577296 rs1407910 0.51 0.424042897 0.4737 hCV2783597 rs1860824 hCV7577311 rs1323473 0.51 0.424042897 0.4249 hCV2783597 rs1860824 hCV7577344 rs876445 0.51 0.424042897 1 hCV2783604 rs10760126 hCV11266229 rs10435844 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV11266268 rs10760121 0.51 0.330072784 0.6526 hCV2783604 rs10760126 hCV11720351 rs1885995 0.51 0.330072784 0.4639 hCV2783604 rs10760126 hCV11720413 rs1930782 0.51 0.330072784 1 hCV2783604 rs10760126 hCV11720414 rs1930781 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV1452630 rs10818476 0.51 0.330072784 0.362 hCV2783604 rs10760126 hCV1452651 rs3793638 0.51 0.330072784 0.3397 hCV2783604 rs10760126 hCV1452652 rs1060817 0.51 0.330072784 0.3397 hCV2783604 rs10760126 hCV1452665 rs4837796 0.51 0.330072784 0.362 hCV2783604 rs10760126 hCV15751717 rs2296077 0.51 0.330072784 0.404 hCV2783604 rs10760126 hCV15751719 rs2146838 0.51 0.330072784 0.4639 hCV2783604 rs10760126 hCV15757738 rs2302498 0.51 0.330072784 0.4182 hCV2783604 rs10760126 hCV15849116 rs2900180 0.51 0.330072784 0.6795 hCV2783604 rs10760126 hCV15870898 rs2072438 0.51 0.330072784 0.9666 hCV2783604 rs10760126 hCV16124825 rs2109895 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV16175379 rs2239657 0.51 0.330072784 0.6641 hCV2783604 rs10760126 hCV16234795 rs2416804 0.51 0.330072784 0.9666 hCV2783604 rs10760126 hCV1761888 rs1953126 0.51 0.330072784 0.6526 hCV2783604 rs10760126 hCV1761891 rs1930778 0.51 0.330072784 0.5969 hCV2783604 rs10760126 hCV1761894 rs1609810 0.51 0.330072784 0.6271 hCV2783604 rs10760126 hCV22272588 rs10760117 0.51 0.330072784 0.362 hCV2783604 rs10760126 hCV2359565 rs1014530 0.51 0.330072784 1 hCV2783604 rs10760126 hCV25751916 rs10985070 0.51 0.330072784 0.9666 hCV2783604 rs10760126 hCV26144307 rs1016468 0.51 0.330072784 0.4639 hCV2783604 rs10760126 hCV26144332 rs4837813 0.51 0.330072784 0.4432 hCV2783604 rs10760126 hCV2783582 rs10818482 0.51 0.330072784 0.9666 hCV2783604 rs10760126 hCV2783586 rs2270231 0.51 0.330072784 0.6526 hCV2783604 rs10760126 hCV2783589 rs881375 0.51 0.330072784 0.6526 hCV2783604 rs10760126 hCV2783590 rs6478486 0.51 0.330072784 0.6526 hCV2783604 rs10760126 hCV2783591 rs1468671 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783593 rs1548783 0.51 0.330072784 0.6834 hCV2783604 rs10760126 hCV2783597 rs1860824 0.51 0.330072784 0.6773 hCV2783604 rs10760126 hCV2783599 rs7046108 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783607 rs9886724 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783608 rs4836834 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783609 rs2241003 0.51 0.330072784 0.7286 hCV2783604 rs10760126 hCV2783611 rs10435843 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783618 rs2239658 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783620 rs7021880 0.51 0.330072784 0.6261 hCV2783604 rs10760126 hCV2783621 rs2416805 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783622 rs758959 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783625 rs10118357 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783630 rs2269060 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783633 rs7021049 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783634 rs1014529 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783635 rs1930780 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783638 rs3761846 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783640 rs3761847 0.51 0.330072784 0.9666 hCV2783604 rs10760126 hCV2783641 rs2416806 0.51 0.330072784 0.6785 hCV2783604 rs10760126 hCV2783647 rs10739580 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV2783650 rs10760129 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783653 rs10760130 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783655 rs10818488 0.51 0.330072784 1 hCV2783604 rs10760126 hCV2783656 rs4837804 0.51 0.330072784 0.8006 hCV2783604 rs10760126 hCV2783659 rs7039505 0.51 0.330072784 0.6774 hCV2783604 rs10760126 hCV2783711 rs10733650 0.51 0.330072784 0.3631 hCV2783604 rs10760126 hCV2783718 rs10818500 0.51 0.330072784 0.6603 hCV2783604 rs10760126 hCV29005955 rs7036980 0.51 0.330072784 0.3971 hCV2783604 rs10760126 hCV29005976 rs7037195 0.51 0.330072784 1 hCV2783604 rs10760126 hCV29005978 rs7021206 0.51 0.330072784 0.7031 hCV2783604 rs10760126 hCV29006006 rs7034390 0.51 0.330072784 0.6526 hCV2783604 rs10760126 hCV29879049 rs9792437 0.51 0.330072784 0.4385 hCV2783604 rs10760126 hCV3045812 rs7030849 0.51 0.330072784 0.4385 hCV2783604 rs10760126 hCV30829523 rs12343516 0.51 0.330072784 0.3397 hCV2783604 rs10760126 hCV30830319 rs7037673 0.51 0.330072784 0.5102 hCV2783604 rs10760126 hCV30830325 rs10818494 0.51 0.330072784 0.4062 hCV2783604 rs10760126 hCV30830340 rs10760134 0.51 0.330072784 0.3861 hCV2783604 rs10760126 hCV30830341 rs7040033 0.51 0.330072784 0.3861 hCV2783604 rs10760126 hCV30830419 rs10985140 0.51 0.330072784 0.6258 hCV2783604 rs10760126 hCV30830474 rs10739590 0.51 0.330072784 0.5091 hCV2783604 rs10760126 hCV30830638 rs10985073 0.51 0.330072784 0.9666 hCV2783604 rs10760126 hCV30830725 rs7864019 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV30830832 rs10733648 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV30830909 rs11794516 0.51 0.330072784 0.9666 hCV2783604 rs10760126 hCV7577254 rs942152 0.51 0.330072784 0.3708 hCV2783604 rs10760126 hCV7577317 rs1323472 0.51 0.330072784 0.6549 hCV2783604 rs10760126 hCV7577331 rs1468673 0.51 0.330072784 0.6549 hCV2783604 rs10760126 hCV7577344 rs876445 0.51 0.330072784 0.6875 hCV2783604 rs10760126 hCV782875 rs746182 0.51 0.330072784 0.4432 hCV2783608 rs4836834 hCV11266229 rs10435844 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV11266268 rs10760121 0.51 0.330072784 0.6344 hCV2783608 rs4836834 hCV11720351 rs1885995 0.51 0.330072784 0.472 hCV2783608 rs4836834 hCV11720402 rs17611 0.51 0.330072784 0.3301 hCV2783608 rs4836834 hCV11720413 rs1930782 0.51 0.330072784 1 hCV2783608 rs4836834 hCV11720414 rs1930781 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV1452630 rs10818476 0.51 0.330072784 0.3495 hCV2783608 rs4836834 hCV1452665 rs4837796 0.51 0.330072784 0.3495 hCV2783608 rs4836834 hCV15751717 rs2296077 0.51 0.330072784 0.4129 hCV2783608 rs4836834 hCV15751719 rs2146838 0.51 0.330072784 0.472 hCV2783608 rs4836834 hCV15757738 rs2302498 0.51 0.330072784 0.4266 hCV2783608 rs4836834 hCV15849116 rs2900180 0.51 0.330072784 0.6587 hCV2783608 rs4836834 hCV15870898 rs2072438 0.51 0.330072784 0.9671 hCV2783608 rs4836834 hCV16124825 rs2109895 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV16175379 rs2239657 0.51 0.330072784 0.6463 hCV2783608 rs4836834 hCV16234785 rs2416811 0.51 0.330072784 0.3301 hCV2783608 rs4836834 hCV16234795 rs2416804 0.51 0.330072784 0.9672 hCV2783608 rs4836834 hCV1761888 rs1953126 0.51 0.330072784 0.6344 hCV2783608 rs4836834 hCV1761891 rs1930778 0.51 0.330072784 0.5775 hCV2783608 rs4836834 hCV1761894 rs1609810 0.51 0.330072784 0.6068 hCV2783608 rs4836834 hCV22272588 rs10760117 0.51 0.330072784 0.3495 hCV2783608 rs4836834 hCV2359565 rs1014530 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2359571 rs25681 0.51 0.330072784 0.3301 hCV2783608 rs4836834 hCV25751916 rs10985070 0.51 0.330072784 0.9671 hCV2783608 rs4836834 hCV26144282 rs10818499 0.51 0.330072784 0.3301 hCV2783608 rs4836834 hCV26144291 rs4570235 0.51 0.330072784 0.3301 hCV2783608 rs4836834 hCV26144307 rs1016468 0.51 0.330072784 0.472 hCV2783608 rs4836834 hCV26144332 rs4837813 0.51 0.330072784 0.4513 hCV2783608 rs4836834 hCV2783582 rs10818482 0.51 0.330072784 0.9671 hCV2783608 rs4836834 hCV2783586 rs2270231 0.51 0.330072784 0.6344 hCV2783608 rs4836834 hCV2783589 rs881375 0.51 0.330072784 0.6344 hCV2783608 rs4836834 hCV2783590 rs6478486 0.51 0.330072784 0.6344 hCV2783608 rs4836834 hCV2783591 rs1468671 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783593 rs1548783 0.51 0.330072784 0.6645 hCV2783608 rs4836834 hCV2783597 rs1860824 0.51 0.330072784 0.6581 hCV2783608 rs4836834 hCV2783599 rs7046108 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783604 rs10760126 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783607 rs9886724 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783609 rs2241003 0.51 0.330072784 0.7074 hCV2783608 rs4836834 hCV2783611 rs10435843 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783618 rs2239658 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783620 rs7021880 0.51 0.330072784 0.6088 hCV2783608 rs4836834 hCV2783621 rs2416805 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783622 rs758959 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783625 rs10118357 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783630 rs2269060 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783633 rs7021049 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783634 rs1014529 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783635 rs1930780 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783638 rs3761846 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783640 rs3761847 0.51 0.330072784 0.9672 hCV2783608 rs4836834 hCV2783641 rs2416806 0.51 0.330072784 0.6594 hCV2783608 rs4836834 hCV2783647 rs10739580 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV2783650 rs10760129 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783653 rs10760130 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783655 rs10818488 0.51 0.330072784 1 hCV2783608 rs4836834 hCV2783656 rs4837804 0.51 0.330072784 0.775 hCV2783608 rs4836834 hCV2783659 rs7039505 0.51 0.330072784 0.6562 hCV2783608 rs4836834 hCV2783711 rs10733650 0.51 0.330072784 0.3723 hCV2783608 rs4836834 hCV2783718 rs10818500 0.51 0.330072784 0.6661 hCV2783608 rs4836834 hCV29005955 rs7036980 0.51 0.330072784 0.4056 hCV2783608 rs4836834 hCV29005976 rs7037195 0.51 0.330072784 1 hCV2783608 rs4836834 hCV29005978 rs7021206 0.51 0.330072784 0.7031 hCV2783608 rs4836834 hCV29006006 rs7034390 0.51 0.330072784 0.6344 hCV2783608 rs4836834 hCV29879049 rs9792437 0.51 0.330072784 0.4468 hCV2783608 rs4836834 hCV3045812 rs7030849 0.51 0.330072784 0.4468 hCV2783608 rs4836834 hCV30830319 rs7037673 0.51 0.330072784 0.517 hCV2783608 rs4836834 hCV30830325 rs10818494 0.51 0.330072784 0.4154 hCV2783608 rs4836834 hCV30830340 rs10760134 0.51 0.330072784 0.3949 hCV2783608 rs4836834 hCV30830341 rs7040033 0.51 0.330072784 0.3949 hCV2783608 rs4836834 hCV30830419 rs10985140 0.51 0.330072784 0.6317 hCV2783608 rs4836834 hCV30830474 rs10739590 0.51 0.330072784 0.5169 hCV2783608 rs4836834 hCV30830638 rs10985073 0.51 0.330072784 0.9671 hCV2783608 rs4836834 hCV30830725 rs7864019 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV30830832 rs10733648 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV30830909 rs11794516 0.51 0.330072784 0.9671 hCV2783608 rs4836834 hCV7577254 rs942152 0.51 0.330072784 0.3797 hCV2783608 rs4836834 hCV7577317 rs1323472 0.51 0.330072784 0.6604 hCV2783608 rs4836834 hCV7577331 rs1468673 0.51 0.330072784 0.6604 hCV2783608 rs4836834 hCV7577337 rs993247 0.51 0.330072784 0.3301 hCV2783608 rs4836834 hCV7577344 rs876445 0.51 0.330072784 0.6687 hCV2783608 rs4836834 hCV782875 rs746182 0.51 0.330072784 0.4513 hCV2783618 rs2239658 hCV11266229 rs10435844 0.51 0.423423973 1 hCV2783618 rs2239658 hCV11266268 rs10760121 0.51 0.423423973 0.9666 hCV2783618 rs2239658 hCV11720350 rs2057469 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV11720413 rs1930782 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV11720414 rs1930781 0.51 0.423423973 1 hCV2783618 rs2239658 hCV15849105 rs2900185 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV15849116 rs2900180 0.51 0.423423973 1 hCV2783618 rs2239658 hCV15870898 rs2072438 0.51 0.423423973 0.6467 hCV2783618 rs2239658 hCV16124825 rs2109895 0.51 0.423423973 1 hCV2783618 rs2239658 hCV16175379 rs2239657 0.51 0.423423973 0.9664 hCV2783618 rs2239658 hCV16234795 rs2416804 0.51 0.423423973 0.6341 hCV2783618 rs2239658 hCV16234838 rs2416819 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV16234840 rs2416817 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV1632195 rs1998505 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV1761888 rs1953126 0.51 0.423423973 0.9666 hCV2783618 rs2239658 hCV1761891 rs1930778 0.51 0.423423973 0.9602 hCV2783618 rs2239658 hCV1761894 rs1609810 0.51 0.423423973 0.9609 hCV2783618 rs2239658 hCV2359565 rs1014530 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV25613469 rs10760157 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV25751916 rs10985070 0.51 0.423423973 0.6467 hCV2783618 rs2239658 hCV25771057 rs10760150 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV2783582 rs10818482 0.51 0.423423973 0.6467 hCV2783618 rs2239658 hCV2783586 rs2270231 0.51 0.423423973 0.9666 hCV2783618 rs2239658 hCV2783589 rs881375 0.51 0.423423973 0.9666 hCV2783618 rs2239658 hCV2783590 rs6478486 0.51 0.423423973 0.9666 hCV2783618 rs2239658 hCV2783591 rs1468671 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783593 rs1548783 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783597 rs1860824 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783599 rs7046108 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783604 rs10760126 0.51 0.423423973 0.6875 hCV2783618 rs2239658 hCV2783607 rs9886724 0.51 0.423423973 0.6785 hCV2783618 rs2239658 hCV2783608 rs4836834 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV2783609 rs2241003 0.51 0.423423973 0.9321 hCV2783618 rs2239658 hCV2783611 rs10435843 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783620 rs7021880 0.51 0.423423973 0.9301 hCV2783618 rs2239658 hCV2783621 rs2416805 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783622 rs758959 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783625 rs10118357 0.51 0.423423973 0.6645 hCV2783618 rs2239658 hCV2783630 rs2269060 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV2783633 rs7021049 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV2783634 rs1014529 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783635 rs1930780 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783638 rs3761846 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV2783640 rs3761847 0.51 0.423423973 0.6341 hCV2783618 rs2239658 hCV2783641 rs2416806 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783647 rs10739580 0.51 0.423423973 1 hCV2783618 rs2239658 hCV2783650 rs10760129 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV2783653 rs10760130 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV2783655 rs10818488 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV2783656 rs4837804 0.51 0.423423973 0.8956 hCV2783618 rs2239658 hCV2783659 rs7039505 0.51 0.423423973 1 hCV2783618 rs2239658 hCV27912350 rs4837808 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV27912351 rs4837809 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV29005923 rs6478494 0.51 0.423423973 0.4238 hCV2783618 rs2239658 hCV29005924 rs7031128 0.51 0.423423973 0.4264 hCV2783618 rs2239658 hCV29005976 rs7037195 0.51 0.423423973 0.6687 hCV2783618 rs2239658 hCV29005978 rs7021206 0.51 0.423423973 1 hCV2783618 rs2239658 hCV29006006 rs7034390 0.51 0.423423973 0.9666 hCV2783618 rs2239658 hCV30059070 rs10156413 0.51 0.423423973 0.5258 hCV2783618 rs2239658 hCV3045792 rs6478499 0.51 0.423423973 0.4879 hCV2783618 rs2239658 hCV3045801 rs2057465 0.51 0.423423973 0.4332 hCV2783618 rs2239658 hCV30563729 rs9299273 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV30830468 rs10818507 0.51 0.423423973 0.4539 hCV2783618 rs2239658 hCV30830473 rs7036649 0.51 0.423423973 0.4705 hCV2783618 rs2239658 hCV30830475 rs10733652 0.51 0.423423973 0.4269 hCV2783618 rs2239658 hCV30830484 rs10818508 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV30830486 rs10760149 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV30830503 rs4837811 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV30830512 rs10818512 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV30830521 rs10818513 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV30830536 rs7047038 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV30830638 rs10985073 0.51 0.423423973 0.6467 hCV2783618 rs2239658 hCV30830725 rs7864019 0.51 0.423423973 1 hCV2783618 rs2239658 hCV30830832 rs10733648 0.51 0.423423973 1 hCV2783618 rs2239658 hCV30830909 rs11794516 0.51 0.423423973 0.6467 hCV2783618 rs2239658 hCV7577250 rs942153 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV7577271 rs1535655 0.51 0.423423973 0.4465 hCV2783618 rs2239658 hCV7577287 rs1323478 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV7577296 rs1407910 0.51 0.423423973 0.4708 hCV2783618 rs2239658 hCV7577344 rs876445 0.51 0.423423973 1 hCV2783620 rs7021880 hCV11266229 rs10435844 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV11266268 rs10760121 0.51 0.304581904 0.8974 hCV2783620 rs7021880 hCV11720348 rs2057470 0.51 0.304581904 0.3276 hCV2783620 rs7021880 hCV11720350 rs2057469 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV11720386 rs1998506 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV11720394 rs1924081 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV11720413 rs1930782 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV11720414 rs1930781 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV1452630 rs10818476 0.51 0.304581904 0.3276 hCV2783620 rs7021880 hCV1452665 rs4837796 0.51 0.304581904 0.3276 hCV2783620 rs7021880 hCV15849105 rs2900185 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV15849116 rs2900180 0.51 0.304581904 0.9252 hCV2783620 rs7021880 hCV15870898 rs2072438 0.51 0.304581904 0.5878 hCV2783620 rs7021880 hCV16077967 rs2159776 0.51 0.304581904 0.3489 hCV2783620 rs7021880 hCV16124825 rs2109895 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV16175379 rs2239657 0.51 0.304581904 0.8938 hCV2783620 rs7021880 hCV16180474 rs2273988 0.51 0.304581904 0.3656 hCV2783620 rs7021880 hCV16234795 rs2416804 0.51 0.304581904 0.5724 hCV2783620 rs7021880 hCV16234838 rs2416819 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV16234840 rs2416817 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV1632195 rs1998505 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV1632205 rs10818509 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV1761888 rs1953126 0.51 0.304581904 0.8974 hCV2783620 rs7021880 hCV1761891 rs1930778 0.51 0.304581904 0.919 hCV2783620 rs7021880 hCV1761894 rs1609810 0.51 0.304581904 0.8797 hCV2783620 rs7021880 hCV22272588 rs10760117 0.51 0.304581904 0.3276 hCV2783620 rs7021880 hCV2359565 rs1014530 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV25472748 rs10760138 0.51 0.304581904 0.3378 hCV2783620 rs7021880 hCV25613469 rs10760157 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV25746749 rs7023214 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV25751916 rs10985070 0.51 0.304581904 0.5878 hCV2783620 rs7021880 hCV25771057 rs10760150 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV25969661 rs10818503 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV26144328 rs4836841 0.51 0.304581904 0.3656 hCV2783620 rs7021880 hCV2783582 rs10818482 0.51 0.304581904 0.5878 hCV2783620 rs7021880 hCV2783586 rs2270231 0.51 0.304581904 0.8974 hCV2783620 rs7021880 hCV2783589 rs881375 0.51 0.304581904 0.8974 hCV2783620 rs7021880 hCV2783590 rs6478486 0.51 0.304581904 0.8974 hCV2783620 rs7021880 hCV2783591 rs1468671 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783593 rs1548783 0.51 0.304581904 0.9293 hCV2783620 rs7021880 hCV2783597 rs1860824 0.51 0.304581904 0.9627 hCV2783620 rs7021880 hCV2783599 rs7046108 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783604 rs10760126 0.51 0.304581904 0.6261 hCV2783620 rs7021880 hCV2783607 rs9886724 0.51 0.304581904 0.6151 hCV2783620 rs7021880 hCV2783608 rs4836834 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783609 rs2241003 0.51 0.304581904 0.8611 hCV2783620 rs7021880 hCV2783611 rs10435843 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783618 rs2239658 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783621 rs2416805 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783622 rs758959 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783625 rs10118357 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783630 rs2269060 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783633 rs7021049 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783634 rs1014529 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783635 rs1930780 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783638 rs3761846 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783640 rs3761847 0.51 0.304581904 0.5724 hCV2783620 rs7021880 hCV2783641 rs2416806 0.51 0.304581904 0.9275 hCV2783620 rs7021880 hCV2783647 rs10739580 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV2783650 rs10760129 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783653 rs10760130 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783655 rs10818488 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV2783656 rs4837804 0.51 0.304581904 0.8278 hCV2783620 rs7021880 hCV2783659 rs7039505 0.51 0.304581904 0.9186 hCV2783620 rs7021880 hCV2783699 rs10760135 0.51 0.304581904 0.321 hCV2783620 rs7021880 hCV2783718 rs10818500 0.51 0.304581904 0.3411 hCV2783620 rs7021880 hCV27912350 rs4837808 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV27912351 rs4837809 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV29005922 rs7033790 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV29005923 rs6478494 0.51 0.304581904 0.3617 hCV2783620 rs7021880 hCV29005924 rs7031128 0.51 0.304581904 0.3572 hCV2783620 rs7021880 hCV29005931 rs6478496 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV29005938 rs7856420 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV29005976 rs7037195 0.51 0.304581904 0.6088 hCV2783620 rs7021880 hCV29005978 rs7021206 0.51 0.304581904 0.9271 hCV2783620 rs7021880 hCV29006006 rs7034390 0.51 0.304581904 0.8974 hCV2783620 rs7021880 hCV30059070 rs10156413 0.51 0.304581904 0.4923 hCV2783620 rs7021880 hCV30293181 rs10081760 0.51 0.304581904 0.3856 hCV2783620 rs7021880 hCV3045792 rs6478499 0.51 0.304581904 0.4822 hCV2783620 rs7021880 hCV3045801 rs2057465 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV3045802 rs2057466 0.51 0.304581904 0.3656 hCV2783620 rs7021880 hCV3045803 rs2146836 0.51 0.304581904 0.3656 hCV2783620 rs7021880 hCV30527383 rs9644911 0.51 0.304581904 0.3609 hCV2783620 rs7021880 hCV30563728 rs10156396 0.51 0.304581904 0.3378 hCV2783620 rs7021880 hCV30563729 rs9299273 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV30830319 rs7037673 0.51 0.304581904 0.3171 hCV2783620 rs7021880 hCV30830339 rs10818495 0.51 0.304581904 0.3411 hCV2783620 rs7021880 hCV30830342 rs7040319 0.51 0.304581904 0.359 hCV2783620 rs7021880 hCV30830395 rs10985132 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV30830396 rs10739584 0.51 0.304581904 0.3193 hCV2783620 rs7021880 hCV30830397 rs10760139 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV30830406 rs7040603 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV30830407 rs10739585 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV30830414 rs7871371 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV30830417 rs7029523 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV30830419 rs10985140 0.51 0.304581904 0.3342 hCV2783620 rs7021880 hCV30830435 rs10739586 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV30830458 rs10733651 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV30830468 rs10818507 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV30830473 rs7036649 0.51 0.304581904 0.4545 hCV2783620 rs7021880 hCV30830475 rs10733652 0.51 0.304581904 0.3957 hCV2783620 rs7021880 hCV30830484 rs10818508 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV30830486 rs10760149 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV30830503 rs4837811 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV30830512 rs10818512 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV30830521 rs10818513 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV30830536 rs7047038 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV30830538 rs10760152 0.51 0.304581904 0.3778 hCV2783620 rs7021880 hCV30830638 rs10985073 0.51 0.304581904 0.5878 hCV2783620 rs7021880 hCV30830725 rs7864019 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV30830832 rs10733648 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV30830909 rs11794516 0.51 0.304581904 0.5878 hCV2783620 rs7021880 hCV7577250 rs942153 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV7577271 rs1535655 0.51 0.304581904 0.438 hCV2783620 rs7021880 hCV7577286 rs1407912 0.51 0.304581904 0.388 hCV2783620 rs7021880 hCV7577287 rs1323478 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV7577296 rs1407910 0.51 0.304581904 0.4634 hCV2783620 rs7021880 hCV7577311 rs1323473 0.51 0.304581904 0.3885 hCV2783620 rs7021880 hCV7577317 rs1323472 0.51 0.304581904 0.3511 hCV2783620 rs7021880 hCV7577328 rs1323476 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV7577331 rs1468673 0.51 0.304581904 0.3511 hCV2783620 rs7021880 hCV7577332 rs1468672 0.51 0.304581904 0.3506 hCV2783620 rs7021880 hCV7577344 rs876445 0.51 0.304581904 0.9301 hCV2783620 rs7021880 hCV782872 rs758958 0.51 0.304581904 0.3506 hCV2783621 rs2416805 hCV11266229 rs10435844 0.51 0.411716825 1 hCV2783621 rs2416805 hCV11266268 rs10760121 0.51 0.411716825 0.9666 hCV2783621 rs2416805 hCV11720350 rs2057469 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV11720413 rs1930782 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV11720414 rs1930781 0.51 0.411716825 1 hCV2783621 rs2416805 hCV15849105 rs2900185 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV15849116 rs2900180 0.51 0.411716825 1 hCV2783621 rs2416805 hCV15870898 rs2072438 0.51 0.411716825 0.6467 hCV2783621 rs2416805 hCV16124825 rs2109895 0.51 0.411716825 1 hCV2783621 rs2416805 hCV16175379 rs2239657 0.51 0.411716825 0.9664 hCV2783621 rs2416805 hCV16234795 rs2416804 0.51 0.411716825 0.6341 hCV2783621 rs2416805 hCV16234838 rs2416819 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV16234840 rs2416817 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV1632195 rs1998505 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV1761888 rs1953126 0.51 0.411716825 0.9666 hCV2783621 rs2416805 hCV1761891 rs1930778 0.51 0.411716825 0.9602 hCV2783621 rs2416805 hCV1761894 rs1609810 0.51 0.411716825 0.9609 hCV2783621 rs2416805 hCV2359565 rs1014530 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV25613469 rs10760157 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV25751916 rs10985070 0.51 0.411716825 0.6467 hCV2783621 rs2416805 hCV25771057 rs10760150 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV2783582 rs10818482 0.51 0.411716825 0.6467 hCV2783621 rs2416805 hCV2783586 rs2270231 0.51 0.411716825 0.9666 hCV2783621 rs2416805 hCV2783589 rs881375 0.51 0.411716825 0.9666 hCV2783621 rs2416805 hCV2783590 rs6478486 0.51 0.411716825 0.9666 hCV2783621 rs2416805 hCV2783591 rs1468671 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783593 rs1548783 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783597 rs1860824 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783599 rs7046108 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783604 rs10760126 0.51 0.411716825 0.6875 hCV2783621 rs2416805 hCV2783607 rs9886724 0.51 0.411716825 0.6785 hCV2783621 rs2416805 hCV2783608 rs4836834 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV2783609 rs2241003 0.51 0.411716825 0.9321 hCV2783621 rs2416805 hCV2783611 rs10435843 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783618 rs2239658 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783620 rs7021880 0.51 0.411716825 0.9301 hCV2783621 rs2416805 hCV2783622 rs758959 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783625 rs10118357 0.51 0.411716825 0.6645 hCV2783621 rs2416805 hCV2783630 rs2269060 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV2783633 rs7021049 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV2783634 rs1014529 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783635 rs1930780 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783638 rs3761846 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV2783640 rs3761847 0.51 0.411716825 0.6341 hCV2783621 rs2416805 hCV2783641 rs2416806 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783647 rs10739580 0.51 0.411716825 1 hCV2783621 rs2416805 hCV2783650 rs10760129 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV2783653 rs10760130 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV2783655 rs10818488 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV2783656 rs4837804 0.51 0.411716825 0.8956 hCV2783621 rs2416805 hCV2783659 rs7039505 0.51 0.411716825 1 hCV2783621 rs2416805 hCV27912350 rs4837808 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV27912351 rs4837809 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV29005923 rs6478494 0.51 0.411716825 0.4238 hCV2783621 rs2416805 hCV29005924 rs7031128 0.51 0.411716825 0.4264 hCV2783621 rs2416805 hCV29005976 rs7037195 0.51 0.411716825 0.6687 hCV2783621 rs2416805 hCV29005978 rs7021206 0.51 0.411716825 1 hCV2783621 rs2416805 hCV29006006 rs7034390 0.51 0.411716825 0.9666 hCV2783621 rs2416805 hCV30059070 rs10156413 0.51 0.411716825 0.5258 hCV2783621 rs2416805 hCV3045792 rs6478499 0.51 0.411716825 0.4879 hCV2783621 rs2416805 hCV3045801 rs2057465 0.51 0.411716825 0.4332 hCV2783621 rs2416805 hCV30563729 rs9299273 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV30830414 rs7871371 0.51 0.411716825 0.417 hCV2783621 rs2416805 hCV30830468 rs10818507 0.51 0.411716825 0.4539 hCV2783621 rs2416805 hCV30830473 rs7036649 0.51 0.411716825 0.4705 hCV2783621 rs2416805 hCV30830475 rs10733652 0.51 0.411716825 0.4269 hCV2783621 rs2416805 hCV30830484 rs10818508 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV30830486 rs10760149 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV30830503 rs4837811 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV30830512 rs10818512 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV30830521 rs10818513 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV30830536 rs7047038 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV30830638 rs10985073 0.51 0.411716825 0.6467 hCV2783621 rs2416805 hCV30830725 rs7864019 0.51 0.411716825 1 hCV2783621 rs2416805 hCV30830832 rs10733648 0.51 0.411716825 1 hCV2783621 rs2416805 hCV30830909 rs11794516 0.51 0.411716825 0.6467 hCV2783621 rs2416805 hCV7577250 rs942153 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV7577271 rs1535655 0.51 0.411716825 0.4465 hCV2783621 rs2416805 hCV7577287 rs1323478 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV7577296 rs1407910 0.51 0.411716825 0.4708 hCV2783621 rs2416805 hCV7577344 rs876445 0.51 0.411716825 1 hCV2783625 rs10118357 hCV11266229 rs10435844 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV11266268 rs10760121 0.51 0.313879134 0.6295 hCV2783625 rs10118357 hCV11720351 rs1885995 0.51 0.313879134 0.4886 hCV2783625 rs10118357 hCV11720402 rs17611 0.51 0.313879134 0.3377 hCV2783625 rs10118357 hCV11720413 rs1930782 0.51 0.313879134 1 hCV2783625 rs10118357 hCV11720414 rs1930781 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV1452630 rs10818476 0.51 0.313879134 0.3662 hCV2783625 rs10118357 hCV1452651 rs3793638 0.51 0.313879134 0.3446 hCV2783625 rs10118357 hCV1452652 rs1060817 0.51 0.313879134 0.3446 hCV2783625 rs10118357 hCV1452665 rs4837796 0.51 0.313879134 0.3662 hCV2783625 rs10118357 hCV15751717 rs2296077 0.51 0.313879134 0.4287 hCV2783625 rs10118357 hCV15751719 rs2146838 0.51 0.313879134 0.4886 hCV2783625 rs10118357 hCV15755658 rs2300934 0.51 0.313879134 0.3203 hCV2783625 rs10118357 hCV15757738 rs2302498 0.51 0.313879134 0.4424 hCV2783625 rs10118357 hCV15849116 rs2900180 0.51 0.313879134 0.6587 hCV2783625 rs10118357 hCV15870898 rs2072438 0.51 0.313879134 0.9665 hCV2783625 rs10118357 hCV16124825 rs2109895 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV16175379 rs2239657 0.51 0.313879134 0.6419 hCV2783625 rs10118357 hCV16234785 rs2416811 0.51 0.313879134 0.3377 hCV2783625 rs10118357 hCV16234795 rs2416804 0.51 0.313879134 0.9666 hCV2783625 rs10118357 hCV1761881 rs3933326 0.51 0.313879134 0.3184 hCV2783625 rs10118357 hCV1761888 rs1953126 0.51 0.313879134 0.6295 hCV2783625 rs10118357 hCV1761891 rs1930778 0.51 0.313879134 0.5712 hCV2783625 rs10118357 hCV1761894 rs1609810 0.51 0.313879134 0.6003 hCV2783625 rs10118357 hCV22272588 rs10760117 0.51 0.313879134 0.3662 hCV2783625 rs10118357 hCV2359565 rs1014530 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2359571 rs25681 0.51 0.313879134 0.3377 hCV2783625 rs10118357 hCV25751916 rs10985070 0.51 0.313879134 0.9665 hCV2783625 rs10118357 hCV26144282 rs10818499 0.51 0.313879134 0.3377 hCV2783625 rs10118357 hCV26144291 rs4570235 0.51 0.313879134 0.3377 hCV2783625 rs10118357 hCV26144307 rs1016468 0.51 0.313879134 0.4886 hCV2783625 rs10118357 hCV26144332 rs4837813 0.51 0.313879134 0.4683 hCV2783625 rs10118357 hCV2783582 rs10818482 0.51 0.313879134 0.9665 hCV2783625 rs10118357 hCV2783586 rs2270231 0.51 0.313879134 0.6295 hCV2783625 rs10118357 hCV2783589 rs881375 0.51 0.313879134 0.6295 hCV2783625 rs10118357 hCV2783590 rs6478486 0.51 0.313879134 0.6295 hCV2783625 rs10118357 hCV2783591 rs1468671 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783593 rs1548783 0.51 0.313879134 0.6601 hCV2783625 rs10118357 hCV2783597 rs1860824 0.51 0.313879134 0.6539 hCV2783625 rs10118357 hCV2783599 rs7046108 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783604 rs10760126 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783607 rs9886724 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783608 rs4836834 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783609 rs2241003 0.51 0.313879134 0.7034 hCV2783625 rs10118357 hCV2783611 rs10435843 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783618 rs2239658 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783620 rs7021880 0.51 0.313879134 0.6088 hCV2783625 rs10118357 hCV2783621 rs2416805 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783622 rs758959 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783630 rs2269060 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783633 rs7021049 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783634 rs1014529 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783635 rs1930780 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783638 rs3761846 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783640 rs3761847 0.51 0.313879134 0.9666 hCV2783625 rs10118357 hCV2783641 rs2416806 0.51 0.313879134 0.655 hCV2783625 rs10118357 hCV2783647 rs10739580 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV2783650 rs10760129 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783653 rs10760130 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783655 rs10818488 0.51 0.313879134 1 hCV2783625 rs10118357 hCV2783656 rs4837804 0.51 0.313879134 0.775 hCV2783625 rs10118357 hCV2783659 rs7039505 0.51 0.313879134 0.6519 hCV2783625 rs10118357 hCV2783711 rs10733650 0.51 0.313879134 0.3812 hCV2783625 rs10118357 hCV2783718 rs10818500 0.51 0.313879134 0.6661 hCV2783625 rs10118357 hCV29005933 rs7042135 0.51 0.313879134 0.3203 hCV2783625 rs10118357 hCV29005936 rs6478498 0.51 0.313879134 0.3203 hCV2783625 rs10118357 hCV29005955 rs7036980 0.51 0.313879134 0.4221 hCV2783625 rs10118357 hCV29005976 rs7037195 0.51 0.313879134 1 hCV2783625 rs10118357 hCV29005978 rs7021206 0.51 0.313879134 0.6989 hCV2783625 rs10118357 hCV29006006 rs7034390 0.51 0.313879134 0.6295 hCV2783625 rs10118357 hCV29734592 rs10435889 0.51 0.313879134 0.3247 hCV2783625 rs10118357 hCV29879049 rs9792437 0.51 0.313879134 0.4631 hCV2783625 rs10118357 hCV3045812 rs7030849 0.51 0.313879134 0.4631 hCV2783625 rs10118357 hCV30829523 rs12343516 0.51 0.313879134 0.3446 hCV2783625 rs10118357 hCV30830319 rs7037673 0.51 0.313879134 0.5292 hCV2783625 rs10118357 hCV30830325 rs10818494 0.51 0.313879134 0.4255 hCV2783625 rs10118357 hCV30830340 rs10760134 0.51 0.313879134 0.4048 hCV2783625 rs10118357 hCV30830341 rs7040033 0.51 0.313879134 0.4048 hCV2783625 rs10118357 hCV30830415 rs7855998 0.51 0.313879134 0.3203 hCV2783625 rs10118357 hCV30830419 rs10985140 0.51 0.313879134 0.6251 hCV2783625 rs10118357 hCV30830427 rs10760142 0.51 0.313879134 0.3203 hCV2783625 rs10118357 hCV30830474 rs10739590 0.51 0.313879134 0.5432 hCV2783625 rs10118357 hCV30830638 rs10985073 0.51 0.313879134 0.9665 hCV2783625 rs10118357 hCV30830725 rs7864019 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV30830832 rs10733648 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV30830909 rs11794516 0.51 0.313879134 0.9665 hCV2783625 rs10118357 hCV7577254 rs942152 0.51 0.313879134 0.393 hCV2783625 rs10118357 hCV7577317 rs1323472 0.51 0.313879134 0.6544 hCV2783625 rs10118357 hCV7577331 rs1468673 0.51 0.313879134 0.6544 hCV2783625 rs10118357 hCV7577337 rs993247 0.51 0.313879134 0.3377 hCV2783625 rs10118357 hCV7577344 rs876445 0.51 0.313879134 0.6645 hCV2783625 rs10118357 hCV782875 rs746182 0.51 0.313879134 0.4683 hCV2783633 rs7021049 hCV11266229 rs10435844 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV11266268 rs10760121 0.51 0.313879134 0.6344 hCV2783633 rs7021049 hCV11720351 rs1885995 0.51 0.313879134 0.472 hCV2783633 rs7021049 hCV11720402 rs17611 0.51 0.313879134 0.3301 hCV2783633 rs7021049 hCV11720413 rs1930782 0.51 0.313879134 1 hCV2783633 rs7021049 hCV11720414 rs1930781 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV1452630 rs10818476 0.51 0.313879134 0.3495 hCV2783633 rs7021049 hCV1452651 rs3793638 0.51 0.313879134 0.3281 hCV2783633 rs7021049 hCV1452652 rs1060817 0.51 0.313879134 0.3281 hCV2783633 rs7021049 hCV1452665 rs4837796 0.51 0.313879134 0.3495 hCV2783633 rs7021049 hCV15751717 rs2296077 0.51 0.313879134 0.4129 hCV2783633 rs7021049 hCV15751719 rs2146838 0.51 0.313879134 0.472 hCV2783633 rs7021049 hCV15757738 rs2302498 0.51 0.313879134 0.4266 hCV2783633 rs7021049 hCV15849116 rs2900180 0.51 0.313879134 0.6587 hCV2783633 rs7021049 hCV15870898 rs2072438 0.51 0.313879134 0.9671 hCV2783633 rs7021049 hCV16124825 rs2109895 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV16175379 rs2239657 0.51 0.313879134 0.6463 hCV2783633 rs7021049 hCV16234785 rs2416811 0.51 0.313879134 0.3301 hCV2783633 rs7021049 hCV16234795 rs2416804 0.51 0.313879134 0.9672 hCV2783633 rs7021049 hCV1761881 rs3933326 0.51 0.313879134 0.3254 hCV2783633 rs7021049 hCV1761888 rs1953126 0.51 0.313879134 0.6344 hCV2783633 rs7021049 hCV1761891 rs1930778 0.51 0.313879134 0.5775 hCV2783633 rs7021049 hCV1761894 rs1609810 0.51 0.313879134 0.6068 hCV2783633 rs7021049 hCV22272588 rs10760117 0.51 0.313879134 0.3495 hCV2783633 rs7021049 hCV2359565 rs1014530 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2359571 rs25681 0.51 0.313879134 0.3301 hCV2783633 rs7021049 hCV25751916 rs10985070 0.51 0.313879134 0.9671 hCV2783633 rs7021049 hCV26144282 rs10818499 0.51 0.313879134 0.3301 hCV2783633 rs7021049 hCV26144291 rs4570235 0.51 0.313879134 0.3301 hCV2783633 rs7021049 hCV26144307 rs1016468 0.51 0.313879134 0.472 hCV2783633 rs7021049 hCV26144332 rs4837813 0.51 0.313879134 0.4513 hCV2783633 rs7021049 hCV2783582 rs10818482 0.51 0.313879134 0.9671 hCV2783633 rs7021049 hCV2783586 rs2270231 0.51 0.313879134 0.6344 hCV2783633 rs7021049 hCV2783589 rs881375 0.51 0.313879134 0.6344 hCV2783633 rs7021049 hCV2783590 rs6478486 0.51 0.313879134 0.6344 hCV2783633 rs7021049 hCV2783591 rs1468671 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783593 rs1548783 0.51 0.313879134 0.6645 hCV2783633 rs7021049 hCV2783597 rs1860824 0.51 0.313879134 0.6581 hCV2783633 rs7021049 hCV2783599 rs7046108 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783604 rs10760126 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783607 rs9886724 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783608 rs4836834 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783609 rs2241003 0.51 0.313879134 0.7074 hCV2783633 rs7021049 hCV2783611 rs10435843 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783618 rs2239658 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783620 rs7021880 0.51 0.313879134 0.6088 hCV2783633 rs7021049 hCV2783621 rs2416805 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783622 rs758959 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783625 rs10118357 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783630 rs2269060 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783634 rs1014529 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783635 rs1930780 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783638 rs3761846 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783640 rs3761847 0.51 0.313879134 0.9672 hCV2783633 rs7021049 hCV2783641 rs2416806 0.51 0.313879134 0.6594 hCV2783633 rs7021049 hCV2783647 rs10739580 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV2783650 rs10760129 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783653 rs10760130 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783655 rs10818488 0.51 0.313879134 1 hCV2783633 rs7021049 hCV2783656 rs4837804 0.51 0.313879134 0.775 hCV2783633 rs7021049 hCV2783659 rs7039505 0.51 0.313879134 0.6562 hCV2783633 rs7021049 hCV2783711 rs10733650 0.51 0.313879134 0.3723 hCV2783633 rs7021049 hCV2783718 rs10818500 0.51 0.313879134 0.6661 hCV2783633 rs7021049 hCV29005955 rs7036980 0.51 0.313879134 0.4056 hCV2783633 rs7021049 hCV29005976 rs7037195 0.51 0.313879134 1 hCV2783633 rs7021049 hCV29005978 rs7021206 0.51 0.313879134 0.7031 hCV2783633 rs7021049 hCV29006006 rs7034390 0.51 0.313879134 0.6344 hCV2783633 rs7021049 hCV29734592 rs10435889 0.51 0.313879134 0.3176 hCV2783633 rs7021049 hCV29879049 rs9792437 0.51 0.313879134 0.4468 hCV2783633 rs7021049 hCV3045812 rs7030849 0.51 0.313879134 0.4468 hCV2783633 rs7021049 hCV30829523 rs12343516 0.51 0.313879134 0.3281 hCV2783633 rs7021049 hCV30830319 rs7037673 0.51 0.313879134 0.517 hCV2783633 rs7021049 hCV30830325 rs10818494 0.51 0.313879134 0.4154 hCV2783633 rs7021049 hCV30830340 rs10760134 0.51 0.313879134 0.3949 hCV2783633 rs7021049 hCV30830341 rs7040033 0.51 0.313879134 0.3949 hCV2783633 rs7021049 hCV30830419 rs10985140 0.51 0.313879134 0.6317 hCV2783633 rs7021049 hCV30830474 rs10739590 0.51 0.313879134 0.5169 hCV2783633 rs7021049 hCV30830638 rs10985073 0.51 0.313879134 0.9671 hCV2783633 rs7021049 hCV30830725 rs7864019 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV30830832 rs10733648 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV30830909 rs11794516 0.51 0.313879134 0.9671 hCV2783633 rs7021049 hCV7577254 rs942152 0.51 0.313879134 0.3797 hCV2783633 rs7021049 hCV7577317 rs1323472 0.51 0.313879134 0.6604 hCV2783633 rs7021049 hCV7577331 rs1468673 0.51 0.313879134 0.6604 hCV2783633 rs7021049 hCV7577337 rs993247 0.51 0.313879134 0.3301 hCV2783633 rs7021049 hCV7577344 rs876445 0.51 0.313879134 0.6687 hCV2783633 rs7021049 hCV782875 rs746182 0.51 0.313879134 0.4513 hCV2783634 rs1014529 hCV11266229 rs10435844 0.51 0.411716825 1 hCV2783634 rs1014529 hCV11266268 rs10760121 0.51 0.411716825 0.9666 hCV2783634 rs1014529 hCV11720350 rs2057469 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV11720413 rs1930782 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV11720414 rs1930781 0.51 0.411716825 1 hCV2783634 rs1014529 hCV15849105 rs2900185 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV15849116 rs2900180 0.51 0.411716825 1 hCV2783634 rs1014529 hCV15870898 rs2072438 0.51 0.411716825 0.6467 hCV2783634 rs1014529 hCV16124825 rs2109895 0.51 0.411716825 1 hCV2783634 rs1014529 hCV16175379 rs2239657 0.51 0.411716825 0.9664 hCV2783634 rs1014529 hCV16234795 rs2416804 0.51 0.411716825 0.6341 hCV2783634 rs1014529 hCV16234838 rs2416819 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV16234840 rs2416817 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV1632195 rs1998505 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV1761888 rs1953126 0.51 0.411716825 0.9666 hCV2783634 rs1014529 hCV1761891 rs1930778 0.51 0.411716825 0.9602 hCV2783634 rs1014529 hCV1761894 rs1609810 0.51 0.411716825 0.9609 hCV2783634 rs1014529 hCV2359565 rs1014530 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV25613469 rs10760157 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV25751916 rs10985070 0.51 0.411716825 0.6467 hCV2783634 rs1014529 hCV25771057 rs10760150 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV2783582 rs10818482 0.51 0.411716825 0.6467 hCV2783634 rs1014529 hCV2783586 rs2270231 0.51 0.411716825 0.9666 hCV2783634 rs1014529 hCV2783589 rs881375 0.51 0.411716825 0.9666 hCV2783634 rs1014529 hCV2783590 rs6478486 0.51 0.411716825 0.9666 hCV2783634 rs1014529 hCV2783591 rs1468671 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783593 rs1548783 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783597 rs1860824 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783599 rs7046108 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783604 rs10760126 0.51 0.411716825 0.6875 hCV2783634 rs1014529 hCV2783607 rs9886724 0.51 0.411716825 0.6785 hCV2783634 rs1014529 hCV2783608 rs4836834 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV2783609 rs2241003 0.51 0.411716825 0.9321 hCV2783634 rs1014529 hCV2783611 rs10435843 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783618 rs2239658 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783620 rs7021880 0.51 0.411716825 0.9301 hCV2783634 rs1014529 hCV2783621 rs2416805 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783622 rs758959 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783625 rs10118357 0.51 0.411716825 0.6645 hCV2783634 rs1014529 hCV2783630 rs2269060 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV2783633 rs7021049 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV2783635 rs1930780 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783638 rs3761846 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV2783640 rs3761847 0.51 0.411716825 0.6341 hCV2783634 rs1014529 hCV2783641 rs2416806 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783647 rs10739580 0.51 0.411716825 1 hCV2783634 rs1014529 hCV2783650 rs10760129 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV2783653 rs10760130 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV2783655 rs10818488 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV2783656 rs4837804 0.51 0.411716825 0.8956 hCV2783634 rs1014529 hCV2783659 rs7039505 0.51 0.411716825 1 hCV2783634 rs1014529 hCV27912350 rs4837808 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV27912351 rs4837809 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV29005923 rs6478494 0.51 0.411716825 0.4238 hCV2783634 rs1014529 hCV29005924 rs7031128 0.51 0.411716825 0.4264 hCV2783634 rs1014529 hCV29005976 rs7037195 0.51 0.411716825 0.6687 hCV2783634 rs1014529 hCV29005978 rs7021206 0.51 0.411716825 1 hCV2783634 rs1014529 hCV29006006 rs7034390 0.51 0.411716825 0.9666 hCV2783634 rs1014529 hCV30059070 rs10156413 0.51 0.411716825 0.5258 hCV2783634 rs1014529 hCV3045792 rs6478499 0.51 0.411716825 0.4879 hCV2783634 rs1014529 hCV3045801 rs2057465 0.51 0.411716825 0.4332 hCV2783634 rs1014529 hCV30563729 rs9299273 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV30830414 rs7871371 0.51 0.411716825 0.417 hCV2783634 rs1014529 hCV30830468 rs10818507 0.51 0.411716825 0.4539 hCV2783634 rs1014529 hCV30830473 rs7036649 0.51 0.411716825 0.4705 hCV2783634 rs1014529 hCV30830475 rs10733652 0.51 0.411716825 0.4269 hCV2783634 rs1014529 hCV30830484 rs10818508 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV30830486 rs10760149 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV30830503 rs4837811 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV30830512 rs10818512 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV30830521 rs10818513 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV30830536 rs7047038 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV30830638 rs10985073 0.51 0.411716825 0.6467 hCV2783634 rs1014529 hCV30830725 rs7864019 0.51 0.411716825 1 hCV2783634 rs1014529 hCV30830832 rs10733648 0.51 0.411716825 1 hCV2783634 rs1014529 hCV30830909 rs11794516 0.51 0.411716825 0.6467 hCV2783634 rs1014529 hCV7577250 rs942153 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV7577271 rs1535655 0.51 0.411716825 0.4465 hCV2783634 rs1014529 hCV7577287 rs1323478 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV7577296 rs1407910 0.51 0.411716825 0.4708 hCV2783634 rs1014529 hCV7577344 rs876445 0.51 0.411716825 1 hCV2783638 rs3761846 hCV11266229 rs10435844 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV11266268 rs10760121 0.51 0.329406037 0.6344 hCV2783638 rs3761846 hCV11720351 rs1885995 0.51 0.329406037 0.472 hCV2783638 rs3761846 hCV11720402 rs17611 0.51 0.329406037 0.3301 hCV2783638 rs3761846 hCV11720413 rs1930782 0.51 0.329406037 1 hCV2783638 rs3761846 hCV11720414 rs1930781 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV1452630 rs10818476 0.51 0.329406037 0.3495 hCV2783638 rs3761846 hCV1452665 rs4837796 0.51 0.329406037 0.3495 hCV2783638 rs3761846 hCV15751717 rs2296077 0.51 0.329406037 0.4129 hCV2783638 rs3761846 hCV15751719 rs2146838 0.51 0.329406037 0.472 hCV2783638 rs3761846 hCV15757738 rs2302498 0.51 0.329406037 0.4266 hCV2783638 rs3761846 hCV15849116 rs2900180 0.51 0.329406037 0.6587 hCV2783638 rs3761846 hCV15870898 rs2072438 0.51 0.329406037 0.9671 hCV2783638 rs3761846 hCV16124825 rs2109895 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV16175379 rs2239657 0.51 0.329406037 0.6463 hCV2783638 rs3761846 hCV16234785 rs2416811 0.51 0.329406037 0.3301 hCV2783638 rs3761846 hCV16234795 rs2416804 0.51 0.329406037 0.9672 hCV2783638 rs3761846 hCV1761888 rs1953126 0.51 0.329406037 0.6344 hCV2783638 rs3761846 hCV1761891 rs1930778 0.51 0.329406037 0.5775 hCV2783638 rs3761846 hCV1761894 rs1609810 0.51 0.329406037 0.6068 hCV2783638 rs3761846 hCV22272588 rs10760117 0.51 0.329406037 0.3495 hCV2783638 rs3761846 hCV2359565 rs1014530 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2359571 rs25681 0.51 0.329406037 0.3301 hCV2783638 rs3761846 hCV25751916 rs10985070 0.51 0.329406037 0.9671 hCV2783638 rs3761846 hCV26144282 rs10818499 0.51 0.329406037 0.3301 hCV2783638 rs3761846 hCV26144291 rs4570235 0.51 0.329406037 0.3301 hCV2783638 rs3761846 hCV26144307 rs1016468 0.51 0.329406037 0.472 hCV2783638 rs3761846 hCV26144332 rs4837813 0.51 0.329406037 0.4513 hCV2783638 rs3761846 hCV2783582 rs10818482 0.51 0.329406037 0.9671 hCV2783638 rs3761846 hCV2783586 rs2270231 0.51 0.329406037 0.6344 hCV2783638 rs3761846 hCV2783589 rs881375 0.51 0.329406037 0.6344 hCV2783638 rs3761846 hCV2783590 rs6478486 0.51 0.329406037 0.6344 hCV2783638 rs3761846 hCV2783591 rs1468671 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783593 rs1548783 0.51 0.329406037 0.6645 hCV2783638 rs3761846 hCV2783597 rs1860824 0.51 0.329406037 0.6581 hCV2783638 rs3761846 hCV2783599 rs7046108 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783604 rs10760126 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783607 rs9886724 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783608 rs4836834 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783609 rs2241003 0.51 0.329406037 0.7074 hCV2783638 rs3761846 hCV2783611 rs10435843 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783618 rs2239658 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783620 rs7021880 0.51 0.329406037 0.6088 hCV2783638 rs3761846 hCV2783621 rs2416805 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783622 rs758959 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783625 rs10118357 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783630 rs2269060 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783633 rs7021049 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783634 rs1014529 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783635 rs1930780 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783640 rs3761847 0.51 0.329406037 0.9672 hCV2783638 rs3761846 hCV2783641 rs2416806 0.51 0.329406037 0.6594 hCV2783638 rs3761846 hCV2783647 rs10739580 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV2783650 rs10760129 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783653 rs10760130 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783655 rs10818488 0.51 0.329406037 1 hCV2783638 rs3761846 hCV2783656 rs4837804 0.51 0.329406037 0.775 hCV2783638 rs3761846 hCV2783659 rs7039505 0.51 0.329406037 0.6562 hCV2783638 rs3761846 hCV2783711 rs10733650 0.51 0.329406037 0.3723 hCV2783638 rs3761846 hCV2783718 rs10818500 0.51 0.329406037 0.6661 hCV2783638 rs3761846 hCV29005955 rs7036980 0.51 0.329406037 0.4056 hCV2783638 rs3761846 hCV29005976 rs7037195 0.51 0.329406037 1 hCV2783638 rs3761846 hCV29005978 rs7021206 0.51 0.329406037 0.7031 hCV2783638 rs3761846 hCV29006006 rs7034390 0.51 0.329406037 0.6344 hCV2783638 rs3761846 hCV29879049 rs9792437 0.51 0.329406037 0.4468 hCV2783638 rs3761846 hCV3045812 rs7030849 0.51 0.329406037 0.4468 hCV2783638 rs3761846 hCV30830319 rs7037673 0.51 0.329406037 0.517 hCV2783638 rs3761846 hCV30830325 rs10818494 0.51 0.329406037 0.4154 hCV2783638 rs3761846 hCV30830340 rs10760134 0.51 0.329406037 0.3949 hCV2783638 rs3761846 hCV30830341 rs7040033 0.51 0.329406037 0.3949 hCV2783638 rs3761846 hCV30830419 rs10985140 0.51 0.329406037 0.6317 hCV2783638 rs3761846 hCV30830474 rs10739590 0.51 0.329406037 0.5169 hCV2783638 rs3761846 hCV30830638 rs10985073 0.51 0.329406037 0.9671 hCV2783638 rs3761846 hCV30830725 rs7864019 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV30830832 rs10733648 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV30830909 rs11794516 0.51 0.329406037 0.9671 hCV2783638 rs3761846 hCV7577254 rs942152 0.51 0.329406037 0.3797 hCV2783638 rs3761846 hCV7577317 rs1323472 0.51 0.329406037 0.6604 hCV2783638 rs3761846 hCV7577331 rs1468673 0.51 0.329406037 0.6604 hCV2783638 rs3761846 hCV7577337 rs993247 0.51 0.329406037 0.3301 hCV2783638 rs3761846 hCV7577344 rs876445 0.51 0.329406037 0.6687 hCV2783638 rs3761846 hCV782875 rs746182 0.51 0.329406037 0.4513 hCV2783641 rs2416806 hCV11266229 rs10435844 0.51 0.450433113 1 hCV2783641 rs2416806 hCV11266268 rs10760121 0.51 0.450433113 1 hCV2783641 rs2416806 hCV11720350 rs2057469 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV11720413 rs1930782 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV11720414 rs1930781 0.51 0.450433113 1 hCV2783641 rs2416806 hCV15849105 rs2900185 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV15849116 rs2900180 0.51 0.450433113 1 hCV2783641 rs2416806 hCV15870898 rs2072438 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV16124825 rs2109895 0.51 0.450433113 1 hCV2783641 rs2416806 hCV16175379 rs2239657 0.51 0.450433113 0.9652 hCV2783641 rs2416806 hCV16234795 rs2416804 0.51 0.450433113 0.6235 hCV2783641 rs2416806 hCV16234838 rs2416819 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV16234840 rs2416817 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV1632195 rs1998505 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV1761888 rs1953126 0.51 0.450433113 1 hCV2783641 rs2416806 hCV1761891 rs1930778 0.51 0.450433113 1 hCV2783641 rs2416806 hCV1761894 rs1609810 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2359565 rs1014530 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV25613469 rs10760157 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV25751916 rs10985070 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV25771057 rs10760150 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV2783582 rs10818482 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783586 rs2270231 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783589 rs881375 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783590 rs6478486 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783591 rs1468671 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783593 rs1548783 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783597 rs1860824 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783599 rs7046108 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783604 rs10760126 0.51 0.450433113 0.6785 hCV2783641 rs2416806 hCV2783607 rs9886724 0.51 0.450433113 0.6785 hCV2783641 rs2416806 hCV2783608 rs4836834 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783609 rs2241003 0.51 0.450433113 0.9321 hCV2783641 rs2416806 hCV2783611 rs10435843 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783618 rs2239658 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783620 rs7021880 0.51 0.450433113 0.9275 hCV2783641 rs2416806 hCV2783621 rs2416805 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783622 rs758959 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783625 rs10118357 0.51 0.450433113 0.655 hCV2783641 rs2416806 hCV2783630 rs2269060 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783633 rs7021049 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783634 rs1014529 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783635 rs1930780 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783638 rs3761846 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783640 rs3761847 0.51 0.450433113 0.6235 hCV2783641 rs2416806 hCV2783647 rs10739580 0.51 0.450433113 1 hCV2783641 rs2416806 hCV2783650 rs10760129 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783653 rs10760130 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783655 rs10818488 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV2783656 rs4837804 0.51 0.450433113 0.8918 hCV2783641 rs2416806 hCV2783659 rs7039505 0.51 0.450433113 1 hCV2783641 rs2416806 hCV27912350 rs4837808 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV27912351 rs4837809 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV29005976 rs7037195 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV29005978 rs7021206 0.51 0.450433113 1 hCV2783641 rs2416806 hCV29006006 rs7034390 0.51 0.450433113 1 hCV2783641 rs2416806 hCV30059070 rs10156413 0.51 0.450433113 0.5429 hCV2783641 rs2416806 hCV3045792 rs6478499 0.51 0.450433113 0.4996 hCV2783641 rs2416806 hCV30563729 rs9299273 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV30830468 rs10818507 0.51 0.450433113 0.4643 hCV2783641 rs2416806 hCV30830473 rs7036649 0.51 0.450433113 0.4829 hCV2783641 rs2416806 hCV30830484 rs10818508 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV30830486 rs10760149 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV30830503 rs4837811 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV30830512 rs10818512 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV30830521 rs10818513 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV30830536 rs7047038 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV30830638 rs10985073 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV30830725 rs7864019 0.51 0.450433113 1 hCV2783641 rs2416806 hCV30830832 rs10733648 0.51 0.450433113 1 hCV2783641 rs2416806 hCV30830909 rs11794516 0.51 0.450433113 0.6594 hCV2783641 rs2416806 hCV7577250 rs942153 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV7577271 rs1535655 0.51 0.450433113 0.4561 hCV2783641 rs2416806 hCV7577287 rs1323478 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV7577296 rs1407910 0.51 0.450433113 0.4819 hCV2783641 rs2416806 hCV7577344 rs876445 0.51 0.450433113 1 hCV2783653 rs10760130 hCV11266229 rs10435844 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV11266268 rs10760121 0.51 0.410057696 0.6344 hCV2783653 rs10760130 hCV11720351 rs1885995 0.51 0.410057696 0.472 hCV2783653 rs10760130 hCV11720413 rs1930782 0.51 0.410057696 1 hCV2783653 rs10760130 hCV11720414 rs1930781 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV15751717 rs2296077 0.51 0.410057696 0.4129 hCV2783653 rs10760130 hCV15751719 rs2146838 0.51 0.410057696 0.472 hCV2783653 rs10760130 hCV15757738 rs2302498 0.51 0.410057696 0.4266 hCV2783653 rs10760130 hCV15849116 rs2900180 0.51 0.410057696 0.6587 hCV2783653 rs10760130 hCV15870898 rs2072438 0.51 0.410057696 0.9671 hCV2783653 rs10760130 hCV16124825 rs2109895 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV16175379 rs2239657 0.51 0.410057696 0.6463 hCV2783653 rs10760130 hCV16234795 rs2416804 0.51 0.410057696 0.9672 hCV2783653 rs10760130 hCV1761888 rs1953126 0.51 0.410057696 0.6344 hCV2783653 rs10760130 hCV1761891 rs1930778 0.51 0.410057696 0.5775 hCV2783653 rs10760130 hCV1761894 rs1609810 0.51 0.410057696 0.6068 hCV2783653 rs10760130 hCV2359565 rs1014530 0.51 0.410057696 1 hCV2783653 rs10760130 hCV25751916 rs10985070 0.51 0.410057696 0.9671 hCV2783653 rs10760130 hCV26144307 rs1016468 0.51 0.410057696 0.472 hCV2783653 rs10760130 hCV26144332 rs4837813 0.51 0.410057696 0.4513 hCV2783653 rs10760130 hCV2783582 rs10818482 0.51 0.410057696 0.9671 hCV2783653 rs10760130 hCV2783586 rs2270231 0.51 0.410057696 0.6344 hCV2783653 rs10760130 hCV2783589 rs881375 0.51 0.410057696 0.6344 hCV2783653 rs10760130 hCV2783590 rs6478486 0.51 0.410057696 0.6344 hCV2783653 rs10760130 hCV2783591 rs1468671 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783593 rs1548783 0.51 0.410057696 0.6645 hCV2783653 rs10760130 hCV2783597 rs1860824 0.51 0.410057696 0.6581 hCV2783653 rs10760130 hCV2783599 rs7046108 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783604 rs10760126 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783607 rs9886724 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783608 rs4836834 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783609 rs2241003 0.51 0.410057696 0.7074 hCV2783653 rs10760130 hCV2783611 rs10435843 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783618 rs2239658 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783620 rs7021880 0.51 0.410057696 0.6088 hCV2783653 rs10760130 hCV2783621 rs2416805 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783622 rs758959 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783625 rs10118357 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783630 rs2269060 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783633 rs7021049 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783634 rs1014529 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783635 rs1930780 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783638 rs3761846 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783640 rs3761847 0.51 0.410057696 0.9672 hCV2783653 rs10760130 hCV2783641 rs2416806 0.51 0.410057696 0.6594 hCV2783653 rs10760130 hCV2783647 rs10739580 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV2783650 rs10760129 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783655 rs10818488 0.51 0.410057696 1 hCV2783653 rs10760130 hCV2783656 rs4837804 0.51 0.410057696 0.775 hCV2783653 rs10760130 hCV2783659 rs7039505 0.51 0.410057696 0.6562 hCV2783653 rs10760130 hCV2783718 rs10818500 0.51 0.410057696 0.6661 hCV2783653 rs10760130 hCV29005976 rs7037195 0.51 0.410057696 1 hCV2783653 rs10760130 hCV29005978 rs7021206 0.51 0.410057696 0.7031 hCV2783653 rs10760130 hCV29006006 rs7034390 0.51 0.410057696 0.6344 hCV2783653 rs10760130 hCV29879049 rs9792437 0.51 0.410057696 0.4468 hCV2783653 rs10760130 hCV3045812 rs7030849 0.51 0.410057696 0.4468 hCV2783653 rs10760130 hCV30830319 rs7037673 0.51 0.410057696 0.517 hCV2783653 rs10760130 hCV30830325 rs10818494 0.51 0.410057696 0.4154 hCV2783653 rs10760130 hCV30830419 rs10985140 0.51 0.410057696 0.6317 hCV2783653 rs10760130 hCV30830474 rs10739590 0.51 0.410057696 0.5169 hCV2783653 rs10760130 hCV30830638 rs10985073 0.51 0.410057696 0.9671 hCV2783653 rs10760130 hCV30830725 rs7864019 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV30830832 rs10733648 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV30830909 rs11794516 0.51 0.410057696 0.9671 hCV2783653 rs10760130 hCV7577317 rs1323472 0.51 0.410057696 0.6604 hCV2783653 rs10760130 hCV7577331 rs1468673 0.51 0.410057696 0.6604 hCV2783653 rs10760130 hCV7577344 rs876445 0.51 0.410057696 0.6687 hCV2783653 rs10760130 hCV782875 rs746182 0.51 0.410057696 0.4513 hCV2783655 rs10818488 hCV11266229 rs10435844 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV11266268 rs10760121 0.51 0.366210234 0.6344 hCV2783655 rs10818488 hCV11720351 rs1885995 0.51 0.366210234 0.472 hCV2783655 rs10818488 hCV11720413 rs1930782 0.51 0.366210234 1 hCV2783655 rs10818488 hCV11720414 rs1930781 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV15751717 rs2296077 0.51 0.366210234 0.4129 hCV2783655 rs10818488 hCV15751719 rs2146838 0.51 0.366210234 0.472 hCV2783655 rs10818488 hCV15757738 rs2302498 0.51 0.366210234 0.4266 hCV2783655 rs10818488 hCV15849116 rs2900180 0.51 0.366210234 0.6587 hCV2783655 rs10818488 hCV15870898 rs2072438 0.51 0.366210234 0.9671 hCV2783655 rs10818488 hCV16124825 rs2109895 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV16175379 rs2239657 0.51 0.366210234 0.6463 hCV2783655 rs10818488 hCV16234795 rs2416804 0.51 0.366210234 0.9672 hCV2783655 rs10818488 hCV1761888 rs1953126 0.51 0.366210234 0.6344 hCV2783655 rs10818488 hCV1761891 rs1930778 0.51 0.366210234 0.5775 hCV2783655 rs10818488 hCV1761894 rs1609810 0.51 0.366210234 0.6068 hCV2783655 rs10818488 hCV2359565 rs1014530 0.51 0.366210234 1 hCV2783655 rs10818488 hCV25751916 rs10985070 0.51 0.366210234 0.9671 hCV2783655 rs10818488 hCV26144307 rs1016468 0.51 0.366210234 0.472 hCV2783655 rs10818488 hCV26144332 rs4837813 0.51 0.366210234 0.4513 hCV2783655 rs10818488 hCV2783582 rs10818482 0.51 0.366210234 0.9671 hCV2783655 rs10818488 hCV2783586 rs2270231 0.51 0.366210234 0.6344 hCV2783655 rs10818488 hCV2783589 rs881375 0.51 0.366210234 0.6344 hCV2783655 rs10818488 hCV2783590 rs6478486 0.51 0.366210234 0.6344 hCV2783655 rs10818488 hCV2783591 rs1468671 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783593 rs1548783 0.51 0.366210234 0.6645 hCV2783655 rs10818488 hCV2783597 rs1860824 0.51 0.366210234 0.6581 hCV2783655 rs10818488 hCV2783599 rs7046108 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783604 rs10760126 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783607 rs9886724 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783608 rs4836834 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783609 rs2241003 0.51 0.366210234 0.7074 hCV2783655 rs10818488 hCV2783611 rs10435843 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783618 rs2239658 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783620 rs7021880 0.51 0.366210234 0.6088 hCV2783655 rs10818488 hCV2783621 rs2416805 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783622 rs758959 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783625 rs10118357 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783630 rs2269060 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783633 rs7021049 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783634 rs1014529 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783635 rs1930780 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783638 rs3761846 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783640 rs3761847 0.51 0.366210234 0.9672 hCV2783655 rs10818488 hCV2783641 rs2416806 0.51 0.366210234 0.6594 hCV2783655 rs10818488 hCV2783647 rs10739580 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV2783650 rs10760129 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783653 rs10760130 0.51 0.366210234 1 hCV2783655 rs10818488 hCV2783656 rs4837804 0.51 0.366210234 0.775 hCV2783655 rs10818488 hCV2783659 rs7039505 0.51 0.366210234 0.6562 hCV2783655 rs10818488 hCV2783711 rs10733650 0.51 0.366210234 0.3723 hCV2783655 rs10818488 hCV2783718 rs10818500 0.51 0.366210234 0.6661 hCV2783655 rs10818488 hCV29005955 rs7036980 0.51 0.366210234 0.4056 hCV2783655 rs10818488 hCV29005976 rs7037195 0.51 0.366210234 1 hCV2783655 rs10818488 hCV29005978 rs7021206 0.51 0.366210234 0.7031 hCV2783655 rs10818488 hCV29006006 rs7034390 0.51 0.366210234 0.6344 hCV2783655 rs10818488 hCV29879049 rs9792437 0.51 0.366210234 0.4468 hCV2783655 rs10818488 hCV3045812 rs7030849 0.51 0.366210234 0.4468 hCV2783655 rs10818488 hCV30830319 rs7037673 0.51 0.366210234 0.517 hCV2783655 rs10818488 hCV30830325 rs10818494 0.51 0.366210234 0.4154 hCV2783655 rs10818488 hCV30830340 rs10760134 0.51 0.366210234 0.3949 hCV2783655 rs10818488 hCV30830341 rs7040033 0.51 0.366210234 0.3949 hCV2783655 rs10818488 hCV30830419 rs10985140 0.51 0.366210234 0.6317 hCV2783655 rs10818488 hCV30830474 rs10739590 0.51 0.366210234 0.5169 hCV2783655 rs10818488 hCV30830638 rs10985073 0.51 0.366210234 0.9671 hCV2783655 rs10818488 hCV30830725 rs7864019 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV30830832 rs10733648 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV30830909 rs11794516 0.51 0.366210234 0.9671 hCV2783655 rs10818488 hCV7577254 rs942152 0.51 0.366210234 0.3797 hCV2783655 rs10818488 hCV7577317 rs1323472 0.51 0.366210234 0.6604 hCV2783655 rs10818488 hCV7577331 rs1468673 0.51 0.366210234 0.6604 hCV2783655 rs10818488 hCV7577344 rs876445 0.51 0.366210234 0.6687 hCV2783655 rs10818488 hCV782875 rs746182 0.51 0.366210234 0.4513 hCV2783677 rs2269066 hCV2783682 rs7861142 0.51 0.847112965 1 hCV29005933 rs7042135 hCV11720402 rs17611 0.51 0.926005625 0.9646 hCV29005933 rs7042135 hCV15755658 rs2300934 0.51 0.926005625 1 hCV29005933 rs7042135 hCV16234785 rs2416811 0.51 0.926005625 0.9646 hCV29005933 rs7042135 hCV2359571 rs25681 0.51 0.926005625 0.9646 hCV29005933 rs7042135 hCV26144282 rs10818499 0.51 0.926005625 0.9646 hCV29005933 rs7042135 hCV26144291 rs4570235 0.51 0.926005625 0.9646 hCV29005933 rs7042135 hCV2783711 rs10733650 0.51 0.926005625 0.9646 hCV29005933 rs7042135 hCV29005936 rs6478498 0.51 0.926005625 1 hCV29005933 rs7042135 hCV29734592 rs10435889 0.51 0.926005625 0.9635 hCV29005933 rs7042135 hCV30167357 rs7022941 0.51 0.926005625 0.928 hCV29005933 rs7042135 hCV30830415 rs7855998 0.51 0.926005625 1 hCV29005933 rs7042135 hCV30830427 rs10760142 0.51 0.926005625 1 hCV29005933 rs7042135 hCV7577337 rs993247 0.51 0.926005625 0.9646 hCV29005978 rs7021206 hCV11266229 rs10435844 0.51 0.423423973 1 hCV29005978 rs7021206 hCV11266268 rs10760121 0.51 0.423423973 0.9651 hCV29005978 rs7021206 hCV11720350 rs2057469 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV11720413 rs1930782 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV11720414 rs1930781 0.51 0.423423973 1 hCV29005978 rs7021206 hCV15849105 rs2900185 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV15849116 rs2900180 0.51 0.423423973 1 hCV29005978 rs7021206 hCV15870898 rs2072438 0.51 0.423423973 0.6788 hCV29005978 rs7021206 hCV16124825 rs2109895 0.51 0.423423973 1 hCV29005978 rs7021206 hCV16175379 rs2239657 0.51 0.423423973 0.9649 hCV29005978 rs7021206 hCV16234795 rs2416804 0.51 0.423423973 0.6666 hCV29005978 rs7021206 hCV16234838 rs2416819 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV16234840 rs2416817 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV1632195 rs1998505 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV1761888 rs1953126 0.51 0.423423973 0.9651 hCV29005978 rs7021206 hCV1761891 rs1930778 0.51 0.423423973 0.9582 hCV29005978 rs7021206 hCV1761894 rs1609810 0.51 0.423423973 0.9588 hCV29005978 rs7021206 hCV2359565 rs1014530 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV25613469 rs10760157 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV25751916 rs10985070 0.51 0.423423973 0.6788 hCV29005978 rs7021206 hCV25771057 rs10760150 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV2783582 rs10818482 0.51 0.423423973 0.6788 hCV29005978 rs7021206 hCV2783586 rs2270231 0.51 0.423423973 0.9651 hCV29005978 rs7021206 hCV2783589 rs881375 0.51 0.423423973 0.9651 hCV29005978 rs7021206 hCV2783590 rs6478486 0.51 0.423423973 0.9651 hCV29005978 rs7021206 hCV2783591 rs1468671 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783593 rs1548783 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783597 rs1860824 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783599 rs7046108 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783604 rs10760126 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783607 rs9886724 0.51 0.423423973 0.6941 hCV29005978 rs7021206 hCV2783608 rs4836834 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783609 rs2241003 0.51 0.423423973 0.929 hCV29005978 rs7021206 hCV2783611 rs10435843 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783618 rs2239658 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783620 rs7021880 0.51 0.423423973 0.9271 hCV29005978 rs7021206 hCV2783621 rs2416805 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783622 rs758959 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783625 rs10118357 0.51 0.423423973 0.6989 hCV29005978 rs7021206 hCV2783630 rs2269060 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783633 rs7021049 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783634 rs1014529 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783635 rs1930780 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783638 rs3761846 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783640 rs3761847 0.51 0.423423973 0.6666 hCV29005978 rs7021206 hCV2783641 rs2416806 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783647 rs10739580 0.51 0.423423973 1 hCV29005978 rs7021206 hCV2783650 rs10760129 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783653 rs10760130 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783655 rs10818488 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV2783656 rs4837804 0.51 0.423423973 0.8925 hCV29005978 rs7021206 hCV2783659 rs7039505 0.51 0.423423973 1 hCV29005978 rs7021206 hCV27912350 rs4837808 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV27912351 rs4837809 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV29005923 rs6478494 0.51 0.423423973 0.4284 hCV29005978 rs7021206 hCV29005976 rs7037195 0.51 0.423423973 0.7031 hCV29005978 rs7021206 hCV29006006 rs7034390 0.51 0.423423973 0.9651 hCV29005978 rs7021206 hCV30059070 rs10156413 0.51 0.423423973 0.5069 hCV29005978 rs7021206 hCV3045792 rs6478499 0.51 0.423423973 0.4687 hCV29005978 rs7021206 hCV30563729 rs9299273 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV30830468 rs10818507 0.51 0.423423973 0.4324 hCV29005978 rs7021206 hCV30830473 rs7036649 0.51 0.423423973 0.4503 hCV29005978 rs7021206 hCV30830484 rs10818508 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV30830486 rs10760149 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV30830503 rs4837811 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV30830512 rs10818512 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV30830521 rs10818513 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV30830536 rs7047038 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV30830638 rs10985073 0.51 0.423423973 0.6788 hCV29005978 rs7021206 hCV30830725 rs7864019 0.51 0.423423973 1 hCV29005978 rs7021206 hCV30830832 rs10733648 0.51 0.423423973 1 hCV29005978 rs7021206 hCV30830909 rs11794516 0.51 0.423423973 0.6788 hCV29005978 rs7021206 hCV7577250 rs942153 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV7577271 rs1535655 0.51 0.423423973 0.4264 hCV29005978 rs7021206 hCV7577287 rs1323478 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV7577296 rs1407910 0.51 0.423423973 0.4516 hCV29005978 rs7021206 hCV7577344 rs876445 0.51 0.423423973 1 hCV29006006 rs7034390 hCV11266229 rs10435844 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV11266268 rs10760121 0.51 0.424658012 1 hCV29006006 rs7034390 hCV11720350 rs2057469 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV11720394 rs1924081 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV11720413 rs1930782 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV11720414 rs1930781 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV15849105 rs2900185 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV15849116 rs2900180 0.51 0.424658012 0.9622 hCV29006006 rs7034390 hCV15870898 rs2072438 0.51 0.424658012 0.6691 hCV29006006 rs7034390 hCV16124825 rs2109895 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV16175379 rs2239657 0.51 0.424658012 0.9341 hCV29006006 rs7034390 hCV16234795 rs2416804 0.51 0.424658012 0.6014 hCV29006006 rs7034390 hCV16234838 rs2416819 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV16234840 rs2416817 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV1632195 rs1998505 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV1761888 rs1953126 0.51 0.424658012 1 hCV29006006 rs7034390 hCV1761891 rs1930778 0.51 0.424658012 1 hCV29006006 rs7034390 hCV1761894 rs1609810 0.51 0.424658012 1 hCV29006006 rs7034390 hCV2359565 rs1014530 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV25472748 rs10760138 0.51 0.424658012 0.4328 hCV29006006 rs7034390 hCV25613469 rs10760157 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV25751916 rs10985070 0.51 0.424658012 0.6691 hCV29006006 rs7034390 hCV25771057 rs10760150 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV2783582 rs10818482 0.51 0.424658012 0.6691 hCV29006006 rs7034390 hCV2783586 rs2270231 0.51 0.424658012 1 hCV29006006 rs7034390 hCV2783589 rs881375 0.51 0.424658012 1 hCV29006006 rs7034390 hCV2783590 rs6478486 0.51 0.424658012 1 hCV29006006 rs7034390 hCV2783591 rs1468671 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783593 rs1548783 0.51 0.424658012 0.9661 hCV29006006 rs7034390 hCV2783597 rs1860824 0.51 0.424658012 0.965 hCV29006006 rs7034390 hCV2783599 rs7046108 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783604 rs10760126 0.51 0.424658012 0.6526 hCV29006006 rs7034390 hCV2783607 rs9886724 0.51 0.424658012 0.6785 hCV29006006 rs7034390 hCV2783608 rs4836834 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV2783609 rs2241003 0.51 0.424658012 0.9321 hCV29006006 rs7034390 hCV2783611 rs10435843 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783618 rs2239658 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783620 rs7021880 0.51 0.424658012 0.8974 hCV29006006 rs7034390 hCV2783621 rs2416805 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783622 rs758959 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783625 rs10118357 0.51 0.424658012 0.6295 hCV29006006 rs7034390 hCV2783630 rs2269060 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV2783633 rs7021049 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV2783634 rs1014529 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783635 rs1930780 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783638 rs3761846 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV2783640 rs3761847 0.51 0.424658012 0.6014 hCV29006006 rs7034390 hCV2783641 rs2416806 0.51 0.424658012 1 hCV29006006 rs7034390 hCV2783647 rs10739580 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV2783650 rs10760129 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV2783653 rs10760130 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV2783655 rs10818488 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV2783656 rs4837804 0.51 0.424658012 0.8593 hCV29006006 rs7034390 hCV2783659 rs7039505 0.51 0.424658012 0.9615 hCV29006006 rs7034390 hCV27912350 rs4837808 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV27912351 rs4837809 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV29005922 rs7033790 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV29005923 rs6478494 0.51 0.424658012 0.4648 hCV29006006 rs7034390 hCV29005924 rs7031128 0.51 0.424658012 0.4729 hCV29006006 rs7034390 hCV29005931 rs6478496 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV29005976 rs7037195 0.51 0.424658012 0.6344 hCV29006006 rs7034390 hCV29005978 rs7021206 0.51 0.424658012 0.9651 hCV29006006 rs7034390 hCV30059070 rs10156413 0.51 0.424658012 0.5621 hCV29006006 rs7034390 hCV3045792 rs6478499 0.51 0.424658012 0.5164 hCV29006006 rs7034390 hCV3045801 rs2057465 0.51 0.424658012 0.4611 hCV29006006 rs7034390 hCV30563728 rs10156396 0.51 0.424658012 0.429 hCV29006006 rs7034390 hCV30563729 rs9299273 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV30830395 rs10985132 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV30830397 rs10760139 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV30830406 rs7040603 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV30830407 rs10739585 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV30830414 rs7871371 0.51 0.424658012 0.4541 hCV29006006 rs7034390 hCV30830417 rs7029523 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV30830468 rs10818507 0.51 0.424658012 0.4819 hCV29006006 rs7034390 hCV30830473 rs7036649 0.51 0.424658012 0.5014 hCV29006006 rs7034390 hCV30830475 rs10733652 0.51 0.424658012 0.4539 hCV29006006 rs7034390 hCV30830484 rs10818508 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV30830486 rs10760149 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV30830503 rs4837811 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV30830512 rs10818512 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV30830521 rs10818513 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV30830536 rs7047038 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV30830638 rs10985073 0.51 0.424658012 0.6691 hCV29006006 rs7034390 hCV30830725 rs7864019 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV30830832 rs10733648 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV30830909 rs11794516 0.51 0.424658012 0.6691 hCV29006006 rs7034390 hCV7577250 rs942153 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV7577271 rs1535655 0.51 0.424658012 0.4734 hCV29006006 rs7034390 hCV7577287 rs1323478 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV7577296 rs1407910 0.51 0.424658012 0.4989 hCV29006006 rs7034390 hCV7577311 rs1323473 0.51 0.424658012 0.4466 hCV29006006 rs7034390 hCV7577328 rs1323476 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV7577332 rs1468672 0.51 0.424658012 0.4414 hCV29006006 rs7034390 hCV7577344 rs876445 0.51 0.424658012 0.9666 hCV29006006 rs7034390 hCV782872 rs758958 0.51 0.424658012 0.4414 hCV29824827 rs9657673 hCV11720383 rs1951784 0.51 0.754211179 1 hCV29824827 rs9657673 hCV11720402 rs17611 0.51 0.754211179 0.9251 hCV29824827 rs9657673 hCV15751718 rs2296078 0.51 0.754211179 0.9628 hCV29824827 rs9657673 hCV15755658 rs2300934 0.51 0.754211179 0.8884 hCV29824827 rs9657673 hCV16110109 rs2078141 0.51 0.754211179 0.8177 hCV29824827 rs9657673 hCV16234785 rs2416811 0.51 0.754211179 0.9251 hCV29824827 rs9657673 hCV1632190 rs10760146 0.51 0.754211179 1 hCV29824827 rs9657673 hCV2359571 rs25681 0.51 0.754211179 0.9251 hCV29824827 rs9657673 hCV25968825 rs10818504 0.51 0.754211179 1 hCV29824827 rs9657673 hCV26144282 rs10818499 0.51 0.754211179 0.9251 hCV29824827 rs9657673 hCV26144291 rs4570235 0.51 0.754211179 0.9251 hCV29824827 rs9657673 hCV26144296 rs10760143 0.51 0.754211179 1 hCV29824827 rs9657673 hCV27476319 rs3747843 0.51 0.754211179 0.9628 hCV29824827 rs9657673 hCV2783711 rs10733650 0.51 0.754211179 0.925 hCV29824827 rs9657673 hCV29005933 rs7042135 0.51 0.754211179 0.8884 hCV29824827 rs9657673 hCV29005936 rs6478498 0.51 0.754211179 0.8884 hCV29824827 rs9657673 hCV29734592 rs10435889 0.51 0.754211179 0.9226 hCV29824827 rs9657673 hCV30041036 rs10156476 0.51 0.754211179 1 hCV29824827 rs9657673 hCV30167357 rs7022941 0.51 0.754211179 1 hCV29824827 rs9657673 hCV3045797 rs7036541 0.51 0.754211179 1 hCV29824827 rs9657673 hCV3045800 rs3736855 0.51 0.754211179 1 hCV29824827 rs9657673 hCV3045804 rs2057467 0.51 0.754211179 0.9467 hCV29824827 rs9657673 hCV3045808 rs10818516 0.51 0.754211179 0.9252 hCV29824827 rs9657673 hCV3045810 rs2209076 0.51 0.754211179 0.9274 hCV29824827 rs9657673 hCV30830340 rs10760134 0.51 0.754211179 0.8185 hCV29824827 rs9657673 hCV30830341 rs7040033 0.51 0.754211179 0.8185 hCV29824827 rs9657673 hCV30830415 rs7855998 0.51 0.754211179 0.8884 hCV29824827 rs9657673 hCV30830427 rs10760142 0.51 0.754211179 0.8884 hCV29824827 rs9657673 hCV30830440 rs10760144 0.51 0.754211179 1 hCV29824827 rs9657673 hCV30830506 rs10760151 0.51 0.754211179 1 hCV29824827 rs9657673 hCV30830537 rs10818515 0.51 0.754211179 0.9624 hCV29824827 rs9657673 hCV30830539 rs10760153 0.51 0.754211179 0.9621 hCV29824827 rs9657673 hCV30830540 rs10760154 0.51 0.754211179 0.9628 hCV29824827 rs9657673 hCV30830541 rs10760155 0.51 0.754211179 0.9628 hCV29824827 rs9657673 hCV30830542 rs10760156 0.51 0.754211179 0.9603 hCV29824827 rs9657673 hCV7577235 rs1052508 0.51 0.754211179 0.9628 hCV29824827 rs9657673 hCV7577248 rs1359086 0.51 0.754211179 0.9274 hCV29824827 rs9657673 hCV7577249 rs1359085 0.51 0.754211179 0.9628 hCV29824827 rs9657673 hCV7577337 rs993247 0.51 0.754211179 0.9251 hCV30167357 rs7022941 hCV11720383 rs1951784 0.51 0.885510667 1 hCV30167357 rs7022941 hCV11720402 rs17611 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV15751718 rs2296078 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV15755658 rs2300934 0.51 0.885510667 0.928 hCV30167357 rs7022941 hCV16234785 rs2416811 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV1632190 rs10760146 0.51 0.885510667 1 hCV30167357 rs7022941 hCV2359571 rs25681 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV25968825 rs10818504 0.51 0.885510667 1 hCV30167357 rs7022941 hCV26144282 rs10818499 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV26144291 rs4570235 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV26144296 rs10760143 0.51 0.885510667 1 hCV30167357 rs7022941 hCV27476319 rs3747843 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV2783711 rs10733650 0.51 0.885510667 0.9642 hCV30167357 rs7022941 hCV29005933 rs7042135 0.51 0.885510667 0.928 hCV30167357 rs7022941 hCV29005936 rs6478498 0.51 0.885510667 0.928 hCV30167357 rs7022941 hCV29734592 rs10435889 0.51 0.885510667 0.9632 hCV30167357 rs7022941 hCV29824827 rs9657673 0.51 0.885510667 1 hCV30167357 rs7022941 hCV30041036 rs10156476 0.51 0.885510667 1 hCV30167357 rs7022941 hCV3045797 rs7036541 0.51 0.885510667 1 hCV30167357 rs7022941 hCV3045800 rs3736855 0.51 0.885510667 1 hCV30167357 rs7022941 hCV3045804 rs2057467 0.51 0.885510667 0.9467 hCV30167357 rs7022941 hCV3045808 rs10818516 0.51 0.885510667 0.928 hCV30167357 rs7022941 hCV3045810 rs2209076 0.51 0.885510667 0.9301 hCV30167357 rs7022941 hCV30830415 rs7855998 0.51 0.885510667 0.928 hCV30167357 rs7022941 hCV30830427 rs10760142 0.51 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0.968215659 1 hCV3045797 rs7036541 hCV29824827 rs9657673 0.51 0.968215659 1 hCV3045797 rs7036541 hCV30041036 rs10156476 0.51 0.968215659 1 hCV3045797 rs7036541 hCV30167357 rs7022941 0.51 0.968215659 1 hCV3045797 rs7036541 hCV3045800 rs3736855 0.51 0.968215659 1 hCV3045797 rs7036541 hCV30830440 rs10760144 0.51 0.968215659 1 hCV3045797 rs7036541 hCV30830506 rs10760151 0.51 0.968215659 1 hCV30830506 rs10760151 hCV11720383 rs1951784 0.51 0.852515741 1 hCV30830506 rs10760151 hCV11720402 rs17611 0.51 0.852515741 0.9293 hCV30830506 rs10760151 hCV15751718 rs2296078 0.51 0.852515741 0.9649 hCV30830506 rs10760151 hCV15755658 rs2300934 0.51 0.852515741 0.8947 hCV30830506 rs10760151 hCV16234785 rs2416811 0.51 0.852515741 0.9293 hCV30830506 rs10760151 hCV1632190 rs10760146 0.51 0.852515741 1 hCV30830506 rs10760151 hCV2359571 rs25681 0.51 0.852515741 0.9293 hCV30830506 rs10760151 hCV25968825 rs10818504 0.51 0.852515741 1 hCV30830506 rs10760151 hCV26144282 rs10818499 0.51 0.852515741 0.9293 hCV30830506 rs10760151 hCV26144291 rs4570235 0.51 0.852515741 0.9293 hCV30830506 rs10760151 hCV26144296 rs10760143 0.51 0.852515741 1 hCV30830506 rs10760151 hCV27476319 rs3747843 0.51 0.852515741 0.9649 hCV30830506 rs10760151 hCV2783711 rs10733650 0.51 0.852515741 0.9293 hCV30830506 rs10760151 hCV29005933 rs7042135 0.51 0.852515741 0.8947 hCV30830506 rs10760151 hCV29005936 rs6478498 0.51 0.852515741 0.8947 hCV30830506 rs10760151 hCV29734592 rs10435889 0.51 0.852515741 0.9272 hCV30830506 rs10760151 hCV29824827 rs9657673 0.51 0.852515741 1 hCV30830506 rs10760151 hCV30041036 rs10156476 0.51 0.852515741 1 hCV30830506 rs10760151 hCV30167357 rs7022941 0.51 0.852515741 1 hCV30830506 rs10760151 hCV3045797 rs7036541 0.51 0.852515741 1 hCV30830506 rs10760151 hCV3045800 rs3736855 0.51 0.852515741 1 hCV30830506 rs10760151 hCV3045804 rs2057467 0.51 0.852515741 0.9484 hCV30830506 rs10760151 hCV3045808 rs10818516 0.51 0.852515741 0.9294 hCV30830506 rs10760151 hCV3045810 rs2209076 0.51 0.852515741 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0.367429713 0.4963 hCV30830638 rs10985073 hCV11720413 rs1930782 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV11720414 rs1930781 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV1452630 rs10818476 0.51 0.367429713 0.3756 hCV30830638 rs10985073 hCV1452665 rs4837796 0.51 0.367429713 0.3756 hCV30830638 rs10985073 hCV15751717 rs2296077 0.51 0.367429713 0.4374 hCV30830638 rs10985073 hCV15751719 rs2146838 0.51 0.367429713 0.4963 hCV30830638 rs10985073 hCV15757738 rs2302498 0.51 0.367429713 0.4505 hCV30830638 rs10985073 hCV15849116 rs2900180 0.51 0.367429713 0.6342 hCV30830638 rs10985073 hCV15870898 rs2072438 0.51 0.367429713 1 hCV30830638 rs10985073 hCV16124825 rs2109895 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV16175379 rs2239657 0.51 0.367429713 0.625 hCV30830638 rs10985073 hCV16234795 rs2416804 0.51 0.367429713 0.9353 hCV30830638 rs10985073 hCV1761888 rs1953126 0.51 0.367429713 0.6691 hCV30830638 rs10985073 hCV1761891 rs1930778 0.51 0.367429713 0.6222 hCV30830638 rs10985073 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hCV30830638 rs10985073 hCV2783607 rs9886724 0.51 0.367429713 1 hCV30830638 rs10985073 hCV2783608 rs4836834 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV2783609 rs2241003 0.51 0.367429713 0.7074 hCV30830638 rs10985073 hCV2783611 rs10435843 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV2783618 rs2239658 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV2783620 rs7021880 0.51 0.367429713 0.5878 hCV30830638 rs10985073 hCV2783621 rs2416805 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV2783622 rs758959 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV2783625 rs10118357 0.51 0.367429713 0.9665 hCV30830638 rs10985073 hCV2783630 rs2269060 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV2783633 rs7021049 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV2783634 rs1014529 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV2783635 rs1930780 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV2783638 rs3761846 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV2783640 rs3761847 0.51 0.367429713 0.9353 hCV30830638 rs10985073 hCV2783641 rs2416806 0.51 0.367429713 0.6594 hCV30830638 rs10985073 hCV2783647 rs10739580 0.51 0.367429713 0.6467 hCV30830638 rs10985073 hCV2783650 rs10760129 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV2783653 rs10760130 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV2783655 rs10818488 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV2783656 rs4837804 0.51 0.367429713 0.7472 hCV30830638 rs10985073 hCV2783659 rs7039505 0.51 0.367429713 0.6319 hCV30830638 rs10985073 hCV2783711 rs10733650 0.51 0.367429713 0.3903 hCV30830638 rs10985073 hCV2783718 rs10818500 0.51 0.367429713 0.6972 hCV30830638 rs10985073 hCV29005955 rs7036980 0.51 0.367429713 0.4304 hCV30830638 rs10985073 hCV29005976 rs7037195 0.51 0.367429713 0.9671 hCV30830638 rs10985073 hCV29005978 rs7021206 0.51 0.367429713 0.6788 hCV30830638 rs10985073 hCV29006006 rs7034390 0.51 0.367429713 0.6691 hCV30830638 rs10985073 hCV29879049 rs9792437 0.51 0.367429713 0.4711 hCV30830638 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0.367429713 0.4761 hCV30830641 rs4837839 hCV11266055 rs4837823 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV11493945 rs1865542 0.51 0.518235842 0.8942 hCV30830641 rs4837839 hCV11840647 rs10985194 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219008 rs7028970 0.51 0.518235842 0.8923 hCV30830641 rs4837839 hCV1219009 rs3747850 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219010 rs7870797 0.51 0.518235842 0.8896 hCV30830641 rs4837839 hCV1219011 rs3761856 0.51 0.518235842 0.7553 hCV30830641 rs4837839 hCV1219013 rs10760169 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219014 rs4837832 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219022 rs880823 0.51 0.518235842 0.8139 hCV30830641 rs4837839 hCV1219023 rs878691 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219024 rs10760167 0.51 0.518235842 0.8948 hCV30830641 rs4837839 hCV1219026 rs963003 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219027 rs10818524 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219038 rs10760159 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219040 rs10985188 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219042 rs7865779 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV1219043 rs10760161 0.51 0.518235842 0.9293 hCV30830641 rs4837839 hCV1219044 rs10818517 0.51 0.518235842 0.9293 hCV30830641 rs4837839 hCV1434290 rs2416829 0.51 0.518235842 0.6292 hCV30830641 rs4837839 hCV15830840 rs2149805 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV25988184 rs10985200 0.51 0.518235842 0.8829 hCV30830641 rs4837839 hCV26144347 rs10760158 0.51 0.518235842 0.7446 hCV30830641 rs4837839 hCV26144352 rs10760160 0.51 0.518235842 0.8942 hCV30830641 rs4837839 hCV26144367 rs3827678 0.51 0.518235842 0.8522 hCV30830641 rs4837839 hCV26144368 rs4836845 0.51 0.518235842 0.8888 hCV30830641 rs4837839 hCV27492705 rs3810942 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV27912354 rs4836847 0.51 0.518235842 0.8942 hCV30830641 rs4837839 hCV27912355 rs4837834 0.51 0.518235842 0.7919 hCV30830641 rs4837839 hCV27967328 rs4836848 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV27988905 rs4836843 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV28010799 rs4240466 0.51 0.518235842 0.8948 hCV30830641 rs4837839 hCV28010800 rs4837827 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV28032606 rs4837818 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV28032607 rs4556152 0.51 0.518235842 0.8942 hCV30830641 rs4837839 hCV28032608 rs4837835 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV2973085 rs10818523 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV2973086 rs10513365 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830586 rs10760162 0.51 0.518235842 0.8223 hCV30830641 rs4837839 hCV30830588 rs4837819 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830589 rs10760163 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830590 rs4837820 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830591 rs10760164 0.51 0.518235842 0.8942 hCV30830641 rs4837839 hCV30830597 rs4836842 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830606 rs10739593 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830607 rs10760165 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830609 rs4837826 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV30830616 rs13292100 0.51 0.518235842 0.8619 hCV30830641 rs4837839 hCV578200 rs767769 0.51 0.518235842 0.6913 hCV30830641 rs4837839 hCV7577193 rs913763 0.51 0.518235842 0.8961 hCV30830641 rs4837839 hCV8605563 rs10739594 0.51 0.518235842 0.8961 hCV30830725 rs7864019 hCV11266229 rs10435844 0.51 0.424658012 1 hCV30830725 rs7864019 hCV11266268 rs10760121 0.51 0.424658012 0.9666 hCV30830725 rs7864019 hCV11720350 rs2057469 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV11720413 rs1930782 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV11720414 rs1930781 0.51 0.424658012 1 hCV30830725 rs7864019 hCV15849105 rs2900185 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV15849116 rs2900180 0.51 0.424658012 1 hCV30830725 rs7864019 hCV15870898 rs2072438 0.51 0.424658012 0.6467 hCV30830725 rs7864019 hCV16124825 rs2109895 0.51 0.424658012 1 hCV30830725 rs7864019 hCV16175379 rs2239657 0.51 0.424658012 0.9664 hCV30830725 rs7864019 hCV16234795 rs2416804 0.51 0.424658012 0.6341 hCV30830725 rs7864019 hCV16234838 rs2416819 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV16234840 rs2416817 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV1632195 rs1998505 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV1761888 rs1953126 0.51 0.424658012 0.9666 hCV30830725 rs7864019 hCV1761891 rs1930778 0.51 0.424658012 0.9602 hCV30830725 rs7864019 hCV1761894 rs1609810 0.51 0.424658012 0.9609 hCV30830725 rs7864019 hCV2359565 rs1014530 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV25613469 rs10760157 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV25751916 rs10985070 0.51 0.424658012 0.6467 hCV30830725 rs7864019 hCV25771057 rs10760150 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV2783582 rs10818482 0.51 0.424658012 0.6467 hCV30830725 rs7864019 hCV2783586 rs2270231 0.51 0.424658012 0.9666 hCV30830725 rs7864019 hCV2783589 rs881375 0.51 0.424658012 0.9666 hCV30830725 rs7864019 hCV2783590 rs6478486 0.51 0.424658012 0.9666 hCV30830725 rs7864019 hCV2783591 rs1468671 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783593 rs1548783 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783597 rs1860824 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783599 rs7046108 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783604 rs10760126 0.51 0.424658012 0.6875 hCV30830725 rs7864019 hCV2783607 rs9886724 0.51 0.424658012 0.6785 hCV30830725 rs7864019 hCV2783608 rs4836834 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV2783609 rs2241003 0.51 0.424658012 0.9321 hCV30830725 rs7864019 hCV2783611 rs10435843 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783618 rs2239658 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783620 rs7021880 0.51 0.424658012 0.9301 hCV30830725 rs7864019 hCV2783621 rs2416805 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783622 rs758959 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783625 rs10118357 0.51 0.424658012 0.6645 hCV30830725 rs7864019 hCV2783630 rs2269060 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV2783633 rs7021049 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV2783634 rs1014529 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783635 rs1930780 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783638 rs3761846 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV2783640 rs3761847 0.51 0.424658012 0.6341 hCV30830725 rs7864019 hCV2783641 rs2416806 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783647 rs10739580 0.51 0.424658012 1 hCV30830725 rs7864019 hCV2783650 rs10760129 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV2783653 rs10760130 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV2783655 rs10818488 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV2783656 rs4837804 0.51 0.424658012 0.8956 hCV30830725 rs7864019 hCV2783659 rs7039505 0.51 0.424658012 1 hCV30830725 rs7864019 hCV27912350 rs4837808 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV27912351 rs4837809 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV29005924 rs7031128 0.51 0.424658012 0.4264 hCV30830725 rs7864019 hCV29005976 rs7037195 0.51 0.424658012 0.6687 hCV30830725 rs7864019 hCV29005978 rs7021206 0.51 0.424658012 1 hCV30830725 rs7864019 hCV29006006 rs7034390 0.51 0.424658012 0.9666 hCV30830725 rs7864019 hCV30059070 rs10156413 0.51 0.424658012 0.5258 hCV30830725 rs7864019 hCV3045792 rs6478499 0.51 0.424658012 0.4879 hCV30830725 rs7864019 hCV3045801 rs2057465 0.51 0.424658012 0.4332 hCV30830725 rs7864019 hCV30563729 rs9299273 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV30830468 rs10818507 0.51 0.424658012 0.4539 hCV30830725 rs7864019 hCV30830473 rs7036649 0.51 0.424658012 0.4705 hCV30830725 rs7864019 hCV30830475 rs10733652 0.51 0.424658012 0.4269 hCV30830725 rs7864019 hCV30830484 rs10818508 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV30830486 rs10760149 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV30830503 rs4837811 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV30830512 rs10818512 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV30830521 rs10818513 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV30830536 rs7047038 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV30830638 rs10985073 0.51 0.424658012 0.6467 hCV30830725 rs7864019 hCV30830832 rs10733648 0.51 0.424658012 1 hCV30830725 rs7864019 hCV30830909 rs11794516 0.51 0.424658012 0.6467 hCV30830725 rs7864019 hCV7577250 rs942153 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV7577271 rs1535655 0.51 0.424658012 0.4465 hCV30830725 rs7864019 hCV7577287 rs1323478 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV7577296 rs1407910 0.51 0.424658012 0.4708 hCV30830725 rs7864019 hCV7577344 rs876445 0.51 0.424658012 1 hCV7577317 rs1323472 hCV11720351 rs1885995 0.51 0.765562317 0.78 hCV7577317 rs1323472 hCV15751719 rs2146838 0.51 0.765562317 0.78 hCV7577317 rs1323472 hCV26144307 rs1016468 0.51 0.765562317 0.78 hCV7577317 rs1323472 hCV2783718 rs10818500 0.51 0.765562317 1 hCV7577317 rs1323472 hCV30830419 rs10985140 0.51 0.765562317 0.9672 hCV7577317 rs1323472 hCV30830474 rs10739590 0.51 0.765562317 0.7677 hCV7577317 rs1323472 hCV7577331 rs1468673 0.51 0.765562317 1 hCV7577337 rs993247 hCV11720383 rs1951784 0.51 0.888308233 0.9293 hCV7577337 rs993247 hCV11720402 rs17611 0.51 0.888308233 1 hCV7577337 rs993247 hCV15751718 rs2296078 0.51 0.888308233 0.8957 hCV7577337 rs993247 hCV15755658 rs2300934 0.51 0.888308233 0.9646 hCV7577337 rs993247 hCV16234785 rs2416811 0.51 0.888308233 1 hCV7577337 rs993247 hCV1632190 rs10760146 0.51 0.888308233 0.9293 hCV7577337 rs993247 hCV2359571 rs25681 0.51 0.888308233 1 hCV7577337 rs993247 hCV25968825 rs10818504 0.51 0.888308233 0.9293 hCV7577337 rs993247 hCV26144282 rs10818499 0.51 0.888308233 1 hCV7577337 rs993247 hCV26144291 rs4570235 0.51 0.888308233 1 hCV7577337 rs993247 hCV26144296 rs10760143 0.51 0.888308233 0.9279 hCV7577337 rs993247 hCV27476319 rs3747843 0.51 0.888308233 0.8957 hCV7577337 rs993247 hCV2783711 rs10733650 0.51 0.888308233 1 hCV7577337 rs993247 hCV29005933 rs7042135 0.51 0.888308233 0.9646 hCV7577337 rs993247 hCV29005936 rs6478498 0.51 0.888308233 0.9646 hCV7577337 rs993247 hCV29734592 rs10435889 0.51 0.888308233 1 hCV7577337 rs993247 hCV29824827 rs9657673 0.51 0.888308233 0.9251 hCV7577337 rs993247 hCV30041036 rs10156476 0.51 0.888308233 0.9286 hCV7577337 rs993247 hCV30167357 rs7022941 0.51 0.888308233 0.9642 hCV7577337 rs993247 hCV3045797 rs7036541 0.51 0.888308233 0.9272 hCV7577337 rs993247 hCV3045800 rs3736855 0.51 0.888308233 0.9293 hCV7577337 rs993247 hCV30830340 rs10760134 0.51 0.888308233 0.8956 hCV7577337 rs993247 hCV30830341 rs7040033 0.51 0.888308233 0.8956 hCV7577337 rs993247 hCV30830415 rs7855998 0.51 0.888308233 0.9646 hCV7577337 rs993247 hCV30830427 rs10760142 0.51 0.888308233 0.9646 hCV7577337 rs993247 hCV30830440 rs10760144 0.51 0.888308233 0.9293 hCV7577337 rs993247 hCV30830506 rs10760151 0.51 0.888308233 0.9293 hCV7577337 rs993247 hCV30830537 rs10818515 0.51 0.888308233 0.8946 hCV7577337 rs993247 hCV30830539 rs10760153 0.51 0.888308233 0.9287 hCV7577337 rs993247 hCV30830540 rs10760154 0.51 0.888308233 0.8956 hCV7577337 rs993247 hCV30830541 rs10760155 0.51 0.888308233 0.8957 hCV7577337 rs993247 hCV30830542 rs10760156 0.51 0.888308233 0.8894 hCV7577337 rs993247 hCV7577235 rs1052508 0.51 0.888308233 0.8957 hCV7577337 rs993247 hCV7577249 rs1359085 0.51 0.888308233 0.8957 hCV7577344 rs876445 hCV11266229 rs10435844 0.51 0.411716825 1 hCV7577344 rs876445 hCV11266268 rs10760121 0.51 0.411716825 0.9666 hCV7577344 rs876445 hCV11720350 rs2057469 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV11720413 rs1930782 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV11720414 rs1930781 0.51 0.411716825 1 hCV7577344 rs876445 hCV15849105 rs2900185 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV15849116 rs2900180 0.51 0.411716825 1 hCV7577344 rs876445 hCV15870898 rs2072438 0.51 0.411716825 0.6467 hCV7577344 rs876445 hCV16124825 rs2109895 0.51 0.411716825 1 hCV7577344 rs876445 hCV16175379 rs2239657 0.51 0.411716825 0.9664 hCV7577344 rs876445 hCV16234795 rs2416804 0.51 0.411716825 0.6341 hCV7577344 rs876445 hCV16234838 rs2416819 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV16234840 rs2416817 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV1632195 rs1998505 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV1761888 rs1953126 0.51 0.411716825 0.9666 hCV7577344 rs876445 hCV1761891 rs1930778 0.51 0.411716825 0.9602 hCV7577344 rs876445 hCV1761894 rs1609810 0.51 0.411716825 0.9609 hCV7577344 rs876445 hCV2359565 rs1014530 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV25613469 rs10760157 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV25751916 rs10985070 0.51 0.411716825 0.6467 hCV7577344 rs876445 hCV25771057 rs10760150 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV2783582 rs10818482 0.51 0.411716825 0.6467 hCV7577344 rs876445 hCV2783586 rs2270231 0.51 0.411716825 0.9666 hCV7577344 rs876445 hCV2783589 rs881375 0.51 0.411716825 0.9666 hCV7577344 rs876445 hCV2783590 rs6478486 0.51 0.411716825 0.9666 hCV7577344 rs876445 hCV2783591 rs1468671 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783593 rs1548783 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783597 rs1860824 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783599 rs7046108 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783604 rs10760126 0.51 0.411716825 0.6875 hCV7577344 rs876445 hCV2783607 rs9886724 0.51 0.411716825 0.6785 hCV7577344 rs876445 hCV2783608 rs4836834 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV2783609 rs2241003 0.51 0.411716825 0.9321 hCV7577344 rs876445 hCV2783611 rs10435843 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783618 rs2239658 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783620 rs7021880 0.51 0.411716825 0.9301 hCV7577344 rs876445 hCV2783621 rs2416805 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783622 rs758959 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783625 rs10118357 0.51 0.411716825 0.6645 hCV7577344 rs876445 hCV2783630 rs2269060 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV2783633 rs7021049 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV2783634 rs1014529 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783635 rs1930780 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783638 rs3761846 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV2783640 rs3761847 0.51 0.411716825 0.6341 hCV7577344 rs876445 hCV2783641 rs2416806 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783647 rs10739580 0.51 0.411716825 1 hCV7577344 rs876445 hCV2783650 rs10760129 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV2783653 rs10760130 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV2783655 rs10818488 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV2783656 rs4837804 0.51 0.411716825 0.8956 hCV7577344 rs876445 hCV2783659 rs7039505 0.51 0.411716825 1 hCV7577344 rs876445 hCV27912350 rs4837808 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV27912351 rs4837809 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV29005923 rs6478494 0.51 0.411716825 0.4238 hCV7577344 rs876445 hCV29005924 rs7031128 0.51 0.411716825 0.4264 hCV7577344 rs876445 hCV29005976 rs7037195 0.51 0.411716825 0.6687 hCV7577344 rs876445 hCV29005978 rs7021206 0.51 0.411716825 1 hCV7577344 rs876445 hCV29006006 rs7034390 0.51 0.411716825 0.9666 hCV7577344 rs876445 hCV30059070 rs10156413 0.51 0.411716825 0.5258 hCV7577344 rs876445 hCV3045792 rs6478499 0.51 0.411716825 0.4879 hCV7577344 rs876445 hCV3045801 rs2057465 0.51 0.411716825 0.4332 hCV7577344 rs876445 hCV30563729 rs9299273 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV30830414 rs7871371 0.51 0.411716825 0.417 hCV7577344 rs876445 hCV30830468 rs10818507 0.51 0.411716825 0.4539 hCV7577344 rs876445 hCV30830473 rs7036649 0.51 0.411716825 0.4705 hCV7577344 rs876445 hCV30830475 rs10733652 0.51 0.411716825 0.4269 hCV7577344 rs876445 hCV30830484 rs10818508 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV30830486 rs10760149 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV30830503 rs4837811 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV30830512 rs10818512 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV30830521 rs10818513 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV30830536 rs7047038 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV30830638 rs10985073 0.51 0.411716825 0.6467 hCV7577344 rs876445 hCV30830725 rs7864019 0.51 0.411716825 1 hCV7577344 rs876445 hCV30830832 rs10733648 0.51 0.411716825 1 hCV7577344 rs876445 hCV30830909 rs11794516 0.51 0.411716825 0.6467 hCV7577344 rs876445 hCV7577250 rs942153 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV7577271 rs1535655 0.51 0.411716825 0.4465 hCV7577344 rs876445 hCV7577287 rs1323478 0.51 0.411716825 0.4708 hCV7577344 rs876445 hCV7577296 rs1407910 0.51 0.411716825 0.4708 hCV8780517 rs1056567 hCV1452630 rs10818476 0.51 0.48547946 0.4886 hCV8780517 rs1056567 hCV1452665 rs4837796 0.51 0.48547946 0.4886 hCV8780517 rs1056567 hCV1761881 rs3933326 0.51 0.48547946 0.9646 hCV8780517 rs1056567 hCV22272588 rs10760117 0.51 0.48547946 0.4886 hCV8780517 rs1056567 hCV25612709 rs7026635 0.51 0.48547946 0.7608 hCV8780517 rs1056567 hCV25757804 rs4836833 0.51 0.48547946 1 hCV8780517 rs1056567 hCV8780961 rs914842 0.51 0.48547946 0.5969 hCV8780517 rs1056567 hCV8780962 rs1837 0.51 0.48547946 0.7943 hCV8780962 rs1837 hCV1452630 rs10818476 0.51 0.414165706 0.4622 hCV8780962 rs1837 hCV1452651 rs3793638 0.51 0.414165706 0.4281 hCV8780962 rs1837 hCV1452652 rs1060817 0.51 0.414165706 0.4281 hCV8780962 rs1837 hCV1452665 rs4837796 0.51 0.414165706 0.4622 hCV8780962 rs1837 hCV1761881 rs3933326 0.51 0.414165706 0.7653 hCV8780962 rs1837 hCV22272588 rs10760117 0.51 0.414165706 0.4622 hCV8780962 rs1837 hCV25612709 rs7026635 0.51 0.414165706 0.8902 hCV8780962 rs1837 hCV25757804 rs4836833 0.51 0.414165706 0.7943 hCV8780962 rs1837 hCV26144018 rs10739575 0.51 0.414165706 0.5329 hCV8780962 rs1837 hCV2783659 rs7039505 0.51 0.414165706 0.4242 hCV8780962 rs1837 hCV30829523 rs12343516 0.51 0.414165706 0.4281 hCV8780962 rs1837 hCV8780517 rs1056567 0.51 0.414165706 0.7943 hCV8780962 rs1837 hCV8780961 rs914842 0.51 0.414165706 0.6923

TABLE 5 Minor allele frequencies and allele-based association of chr 9q33 SNPs with RA (SAMPLE SET 1-475 Cases/475 Controls) Position & Case Genotypes Marker Gene Type Alleles^(a) 11 12 22 MAF^(b) HW^(c) rs10984984 MEGF9 intronic T122503297C 4 73 394 0.086 0.766 rs10760112 MEGF9 intronic C122507391T 62 187 223 0.329 0.028 rs10985014 G122538111A 13 117 341 0.152 0.472 rs7026635 FBXW2 intronic G122589848A 40 185 247 0.281 0.568 rs1577001 LOC40237 intronic T122597128C 0 15 457 0.016 1 rs7873274 LOC40237 intronic C122599313T 7 79 384 0.099 0.198 rs10985044 A122603331G 15 119 338 0.158 0.296 rs10760117 PSMD5 intronic T122626558G 99 208 157 0.438 0.059 rs10739575 G122645922A 18 122 332 0.167 0.135 rs933003 A122647650G 0 21 451 0.022 1 rs10985051 C122647701A 15 120 336 0.159 0.301 rs13291973 T122654694G 5 64 403 0.078 0.192 rs1837 PHF19 3′UTR T122658050C 41 194 237 0.292 0.911 rs1056567 PHF19 S181S T122671866C 55 205 212 0.334 0.606 rs10985070 PHF19 intronic C122675942A 99 234 137 0.460 1 rs1953126 T122680321C 61 221 184 0.368 0.765 rs1930777 A122680989G 4 72 396 0.085 0.763 rs1609810 G122682172A 61 222 184 0.368 0.691 rs10985073 T122683676C 101 230 140 0.459 0.711 rs7034390 A122686309T 62 227 183 0.372 0.555 rs10818482 A122687906G 96 235 139 0.454 0.926 rs2270231 C122690803G 62 227 182 0.373 0.555 rs2072438 T122691122C 101 233 138 0.461 0.926 rs881375 T122692719C 62 228 182 0.373 0.555 rs6478486 T122695150C 63 226 182 0.374 0.623 rs1860824 G122699160T 62 226 184 0.371 0.622 rs10760126 T122702439C 101 230 140 0.459 0.711 rs4836834 TRAF1 3′UTR T122705722A 101 231 140 0.459 0.781 rs10435844 TRAF1 intronic G122708020T 62 226 183 0.372 0.622 rs2239657 TRAF1 P340P G122711341A 62 224 184 0.370 0.693 rs12377786 TRAF1 intronic G122711580T 0 4 468 0.004 1 rs2239658 TRAF1 intronic T122711658C 62 225 184 0.370 0.623 rs7021880 TRAF1 intronic C122713711G 51 225 195 0.347 0.265 rs3747841 TRAF1 S170S A122715622G 0 15 455 0.016 1 rs2416804 TRAF1 intronic G122716217C 101 229 142 0.457 0.643 rs2416805 TRAF1 intronic T122716303C 62 227 183 0.372 0.555 rs 876445 TRAF1 intronic A122716923T 62 226 183 0.372 0.622 rs10118357 TRAF1 intronic G122719889A 103 228 140 0.461 0.579 rs2269059 TRAF1 intronic A122722293T 3 74 395 0.085 1 rs2191959 TRAF1 intronic A122723655T 3 74 395 0.085 1 rs7021049 TRAF1 intronic G122723803T 103 229 140 0.461 0.643 rs7021206 TRAF1 intronic G122723978A 62 223 184 0.370 0.693 rs1014529 TRAF1 intronic C122724764G 62 226 183 0.372 0.622 rs1930781 TRAF1 intronic G122727655 A 63 225 183 0.373 0.694 rs1930782 TRAF1 intronic C122727726T 97 234 140 0.454 1 rs3761846 C122729418T 98 234 140 0.456 1 rs2416806 G122730113C 62 224 185 0.369 0.693 rs7864019 A122732689T 61 228 182 0.372 0.490 rs10760130 G122741811A 98 230 141 0.454 0.852 rs10818488 A122744908G 97 233 140 0.454 1 rs2900180 T122746203C 59 222 185 0.365 0.617 rs10760131 G122749962T 0 20 446 0.021 1 rs12004487 C5 intronic C122756502T 5 74 386 0.090 0.407 rs16910233 C5 intronic G122763432C 0 4 468 0.004 1 rs2269066 C5 intronic T122776839C 5 86 381 0.102 1 rs2269067 C5 intronic C122776861G 23 150 299 0.208 0.484 rs2159776 C5 intronic C122795981T 98 242 131 0.465 0.517 rs10760134 C5 intronic C122798246T 80 244 146 0.430 0.222 rs7040033 C5 intronic A122798865G 83 243 146 0.433 0.348 rs10760135 C5 intronic T122802827C 102 233 132 0.468 1 rs17611 C5 I802V A122809021G 80 238 149 0.426 0.395 rs10818496 C5 intronic G122814284A 71 225 176 0.389 1 rs10985126 C5 G385G C122823755T 14 149 309 0.188 0.545 rs993247 C5 intronic G122825070A 77 245 149 0.424 0.186 rs2416811 C5 intronic T122829455C 76 247 146 0.425 0.108 rs10156396 C5 intronic T122830953C 23 182 265 0.243 0.314 rs10985132 C5 intronic T122835515C 23 183 266 0.243 0.261 rs10818499 C5 intronic A122839915T 77 247 148 0.425 0.133 rs9644911 C5 intronic G122848925A 23 185 264 0.245 0.214 rs10739585 C5 intronic G122849360C 23 185 263 0.245 0.214 rs7871371 T122855883C 23 183 265 0.243 0.261 rs7855998 T122855917C 77 249 146 0.427 0.110 rs7029523 T122857434C 22 183 264 0.242 0.208 rs1924081 A122862268T 23 182 266 0.242 0.314 rs1323472 C122866156G 79 247 146 0.429 0.159 rs7042135 T122876474C 77 244 150 0.423 0.219 rs6478498 A122877723G 78 247 147 0.427 0.158 rs7856420 G122878978C 39 219 212 0.316 0.109 rs10739586 T122881893A 40 217 215 0.315 0.166 rs6478499 A122882694G 35 213 223 0.300 0.124 rs4837808 A122886441G 35 214 222 0.301 0.101 rs12685539 CEP110 intronic G122896746T 0 8 464 0.008 1 rs10760146 CEP110 intronic T122896906C 73 248 151 0.417 0.089 rs9299273 CEP110 intronic T122898251A 35 216 217 0.306 0.065 rs9657673 CEP110 intronic T122900196C 72 247 152 0.415 0.089 rs7022941 CEP110 intronic G122907291C 73 248 151 0.417 0.089 rs1998506 CEP110 intronic G122910284A 40 219 213 0.317 0.137 rs4837809 CEP110 intronic T122913032G 36 217 219 0.306 0.083 rs1407910 CEP110 intronic T122915251C 36 216 219 0.306 0.103 rs2146838 CEP110 intronic G122916126A 83 246 143 0.436 0.224 rs1951784 CEP110 intronic G122916272A 74 246 152 0.417 0.131 rs10818508 CEP110 intronic G122922855A 35 215 220 0.303 0.081 rs10081760 CEP110 intronic A122924127G 40 219 212 0.317 0.136 rs2900185 CEP110 intronic A122927191G 36 215 218 0.306 0.103 rs4837811 CEP110 intronic T122941415G 36 216 219 0.306 0.103 rs2068055 CEP110 intronic T122943988A 10 114 346 0.143 0.850 rs10760151 CEP110 intronic G122945183A 78 244 150 0.424 0.221 rs7036541 CEP110 intronic G122945456C 80 243 149 0.427 0.301 rs12683062 CEP110 intronic T122946625G 6 100 366 0.119 1 rs3747843 CEP110 intronic A122954127G 120 246 104 0.517 0.311 rs3736855 CEP110 V1398V A122956841T 80 242 150 0.426 0.346 rs10818512 CEP110 intronic A122957176G 37 214 221 0.305 0.158 rs3736856 CEP110 intronic G122960384A 94 232 142 0.449 1 rs2057466 CEP110 intronic T122966751C 40 219 211 0.318 0.136 rs1535655 CEP110 intronic G122968390A 35 215 220 0.303 0.081 rs2146836 CEP110 intronic A122970117C 40 218 212 0.317 0.137 rs2302498 CEP110 intronic A122976150T 79 241 151 0.424 0.345 rs7047038 RAB14 intronic T122986768G 35 215 221 0.303 0.082 rs10760152 RAB14 intronic A122987806C 37 213 221 0.305 0.158 rs10760153 RAB14 intronic C122988196T 79 243 148 0.427 0.258 rs942152 RAB14 intronic C122991506T 89 242 140 0.446 0.403 rs9408928 RAB14 intronic C122991738T 2 49 421 0.056 0.651 rs9409230 T123007581A 1 49 417 0.055 1 rs7030849 C123009655T 82 246 144 0.434 0.223 rs747846 T123022431G 51 183 238 0.302 0.081 rs12343027 T123027074C 3 48 421 0.057 0.188 rs4837817 C123034984G 11 106 354 0.136 0.331 rs4595204 T123056182A 0 33 439 0.035 1 rs10985196 GSN intronic A123072865C 20 176 275 0.229 0.242 rs306781 GSN intronic C123082765T 0 9 463 0.010 1 rs11787991 GSN intronic T123086454G 1 28 443 0.032 0.379 rs7046030 GSN intronic C123087058T 19 165 283 0.217 0.496 rs12683459 GSN intronic A123088119G 19 170 283 0.220 0.349 rs11788156 GSN intronic C123111661G 0 39 433 0.041 1 rs4837839 GSN intronic T123111948C 94 223 154 0.436 0.453 rs306783 GSN intronic T123112418C 100 235 136 0.462 1 rs306784 GSN intronic T123112473G 69 236 165 0.398 0.336 rs10818527 GSN intronic A123115075G 60 225 186 0.366 0.553 rs16910509 GSN intronic T123123292C 13 98 361 0.131 0.066 rs2304393 GSN G471G T123123435C 1 39 427 0.044 0.601 rs12683989 GSN intronic T123125867C 1 50 421 0.055 1 rs1560980 GSN intronic C123133818G 1 31 439 0.035 0.440 rs7039494 GSN intronic T123134411A 12 136 324 0.169 0.744 rs12340264 STOM intronic T123149742C 6 72 394 0.089 0.246 rs12554081 STOM intronic A123165145C 13 117 342 0.151 0.472 rs17086 STOM intronic G123165341A 68 203 200 0.360 0.162 rs10818531 STOM intronic T123168845C 1 39 432 0.043 0.597 rs367395 STOM intronic T123171333G 9 106 357 0.131 0.688 Control Genotypes Genotypic Marker 11 12 22 MAF HW^(c) OR (95% CI) P^(d) P^(e) rs10984984 3 62 405 0.072 0.725 1.21 (0.86-1.69) 0.2768 0.563 rs10760112 43 163 261 0.267 0.024 1.35 (1.11-1.65) 0.0047 0.018 rs10985014 12 93 364 0.125 0.055 1.26 (0.97-1.63) 0.0991 0.174 rs7026635 31 154 285 0.230 0.117 1.31 (1.06-1.61) 0.0135 0.036 rs1577001 0 18 452 0.019 1 0.83 (0.41-1.65) 0.5864 0.589 rs7873274 7 76 387 0.096 0.175 1.04 (0.76-1.41) 0.8203 0.966 rs10985044 13 97 360 0.131 0.064 1.24 (0.96-1.61) 0.1075 0.218 rs10760117 66 198 199 0.356 0.156 1.40 (1.17-1.69) 6.11E−04 0.003 rs10739575 13 107 348 0.142 0.183 1.21 (0.94-1.56) 0.1428 0.344 rs933003 1 10 458 0.013 0.069 1.76 (0.86-3.59) 0.1263 0.116 rs10985051 14 97 358 0.133 0.028 1.23 (0.95-1.59) 0.1245 0.208 rs13291973 4 55 410 0.067 0.146 1.18 (0.83-1.67) 0.3634 0.664 rs1837 32 152 286 0.230 0.068 1.38 (1.13-1.70) 0.0025 0.005 rs1056567 38 182 250 0.274 0.563 1.32 (1.09-1.61) 0.0059 0.022 rs10985070 69 222 178 0.384 1 1.37 (1.14-1.64) 9.07E−04 0.004 rs1953126 45 197 223 0.309 0.913 1.30 (1.08-1.58) 0.0067 0.023 rs1930777 3 62 404 0.072 0.725 1.18 (0.85-1.66) 0.3277 0.629 rs1609810 43 194 224 0.304 0.912 1.34 (1.10-1.62) 0.0031 0.012 rs10985073 70 220 178 0.385 0.922 1.36 (1.13-1.63) 0.0013 0.006 rs7034390 45 198 227 0.306 0.829 1.34 (1.11-1.62) 0.0026 0.009 rs10818482 66 220 181 0.377 1 1.38 (1.14-1.65) 6.79E−04 0.003 rs2270231 47 197 226 0.310 0.667 1.32 (1.09-1.60) 0.0039 0.012 rs2072438 69 223 176 0.386 1 1.36 (1.13-1.64) 0.0010 0.004 rs881375 47 198 223 0.312 0.747 1.31 (1.08-1.59) 0.0052 0.016 rs6478486 45 197 227 0.306 0.828 1.35 (1.12-1.64) 0.0019 0.007 rs1860824 45 197 228 0.305 0.828 1.34 (1.11-1.62) 0.0026 0.009 rs10760126 68 222 180 0.381 1 1.38 (1.15-1.65) 6.90E−04 0.003 rs4836834 68 222 180 0.381 1 1.38 (1.15-1.66) 6.72E−04 0.003 rs10435844 45 197 228 0.305 0.828 1.35 (1.11-1.63) 0.0024 0.008 rs2239657 45 195 229 0.304 0.743 1.35 (1.11-1.63) 0.0024 0.008 rs12377786 0 3 467 0.003 1 1.33 (0.30-5.95) 0.7085 0.718 rs2239658 45 195 228 0.304 0.743 1.34 (1.11-1.63) 0.0025 0.009 rs7021880 34 187 249 0.271 1 1.43 (1.17-1.74) 3.12E−04 0.001 rs3747841 0 6 464 0.006 1 2.52 (0.98-6.53) 0.0470 0.046 rs2416804 67 221 181 0.378 1 1.38 (1.15-1.66) 6.58E-04 0.003 rs2416805 46 195 229 0.305 0.664 1.35 (1.11-1.63) 0.0023 0.007 rs 876445 45 197 228 0.305 0.828 1.35 (1.11-1.63) 0.0024 0.008 rs10118357 68 222 180 0.381 1 1.39 (1.16-1.67) 5.08E−04 0.002 rs2269059 4 61 405 0.073 0.300 1.17 (0.84-1.63) 0.3656 0.481 rs2191959 3 62 405 0.072 0.725 1.19 (0.85-1.66) 0.3176 0.568 rs7021049 68 222 180 0.381 1 1.39 (1.16-1.67) 4.95E−04 0.002 rs7021206 45 194 228 0.304 0.664 1.34 (1.11-1.63) 0.0026 0.009 rs1014529 45 197 228 0.305 0.828 1.35 (1.11-1.63) 0.0024 0.008 rs1930781 45 197 227 0.306 0.828 1.35 (1.11-1.63) 0.0023 0.008 rs1930782 66 219 183 0.375 1 1.39 (1.15-1.67) 5.03E−04 0.002 rs3761846 68 219 183 0.378 0.845 1.38 (1.15-1.66) 6.53E−04 0.003 rs2416806 45 196 228 0.305 0.745 1.34 (1.10-1.62) 0.0031 0.011 rs7864019 46 196 228 0.306 0.665 1.34 (1.11-1.62) 0.0028 0.008 rs10760130 68 223 177 0.384 0.922 1.34 (1.11-1.61) 0.0020 0.008 rs10818488 68 220 181 0.380 0.922 1.36 (1.13-1.64) 0.0011 0.005 rs2900180 45 194 223 0.307 0.744 1.29 (1.07-1.57) 0.0087 0.026 rs10760131 0 9 451 0.010 1 2.22 (1.01-4.90) 0.0414 0.041 rs12004487 3 67 398 0.078 0.753 1.17 (0.85-1.63) 0.3420 0.608 rs16910233 0 3 465 0.003 1 1.32 (0.30-5.93) 0.7127 0.722 rs2269066 1 67 401 0.074 0.498 1.43 (1.03-1.97) 0.0296 0.063 rs2269067 13 138 317 0.175 0.751 1.23 (0.98-1.55) 0.0756 0.150 rs2159776 87 221 160 0.422 0.507 1.19 (0.99-1.43) 0.0611 0.106 rs10760134 106 233 131 0.473 0.926 0.84 (0.70-1.01) 0.0544 0.095 rs7040033 107 232 131 0.474 0.853 0.85 (0.71-1.02) 0.0700 0.129 rs10760135 87 219 157 0.424 0.506 1.19 (0.99-1.43) 0.0614 0.152 rs17611 106 230 129 0.475 0.853 0.82 (0.68-0.98) 0.0318 0.074 rs10818496 69 205 196 0.365 0.197 1.11 (0.92-1.33) 0.2916 0.363 rs10985126 12 134 323 0.168 0.744 1.14 (0.90-1.44) 0.2731 0.539 rs993247 106 231 132 0.472 0.782 0.82 (0.68-0.98) 0.0316 0.049 rs2416811 108 230 132 0.474 0.711 0.82 (0.68-0.98) 0.0302 0.032 rs10156396 24 150 295 0.211 0.405 1.20 (0.96-1.49) 0.1021 0.096 rs10985132 24 150 295 0.211 0.405 1.20 (0.96-1.49) 0.1013 0.093 rs10818499 106 230 134 0.470 0.711 0.83 (0.69-1.00) 0.0448 0.052 rs9644911 24 150 295 0.211 0.405 1.21 (0.98-1.50) 0.0804 0.069 rs10739585 24 150 295 0.211 0.405 1.21 (0.98-1.51) 0.0761 0.064 rs7871371 25 149 295 0.212 0.271 1.19 (0.96-1.48) 0.1088 0.076 rs7855998 105 231 134 0.469 0.781 0.84 (0.70-1.01) 0.0612 0.064 rs7029523 24 150 295 0.211 0.405 1.19 (0.96-1.48) 0.1074 0.080 rs1924081 24 150 296 0.211 0.405 1.20 (0.96-1.49) 0.1023 0.096 rs1323472 72 211 186 0.378 0.377 1.23 (1.03-1.48) 0.0246 0.019 rs7042135 105 230 133 0.470 0.781 0.82 (0.69-0.99) 0.0360 0.057 rs6478498 105 231 134 0.469 0.781 0.84 (0.70-1.01) 0.0618 0.077 rs7856420 39 192 237 0.288 1 1.14 (0.94-1.39) 0.1860 0.207 rs10739586 39 189 242 0.284 0.821 1.16 (0.95-1.41) 0.1418 0.172 rs6478499 38 182 250 0.274 0.563 1.14 (0.93-1.39) 0.2078 0.130 rs4837808 38 182 250 0.274 0.563 1.14 (0.93-1.39) 0.1897 0.113 rs12685539 1 5 464 0.007 0.022 1.14 (0.41-3.15) 0.8127 0.441 rs10760146 105 228 137 0.466 0.579 0.82 (0.68-0.99) 0.0316 0.026 rs9299273 38 187 245 0.280 0.819 1.13 (0.93-1.38) 0.2112 0.143 rs9657673 106 227 137 0.467 0.517 0.81 (0.67-0.97) 0.0218 0.017 rs7022941 105 226 138 0.465 0.516 0.82 (0.69-0.99) 0.0361 0.025 rs1998506 39 193 238 0.288 1 1.14 (0.94-1.39) 0.1711 0.220 rs4837809 38 187 244 0.280 0.819 1.13 (0.93-1.38) 0.2114 0.165 rs1407910 38 185 246 0.278 0.730 1.14 (0.94-1.39) 0.1830 0.135 rs2146838 77 220 173 0.398 0.631 1.17 (0.98-1.41) 0.0868 0.105 rs1951784 104 229 136 0.466 0.711 0.82 (0.68-0.99) 0.0320 0.038 rs10818508 39 186 245 0.281 0.649 1.11 (0.91-1.36) 0.2790 0.162 rs10081760 37 194 239 0.285 0.822 1.17 (0.96-1.42) 0.1186 0.198 rs2900185 37 187 246 0.278 0.908 1.15 (0.94-1.40) 0.1694 0.162 rs4837811 38 187 244 0.280 0.819 1.13 (0.93-1.38) 0.2191 0.176 rs2068055 12 103 354 0.135 0.170 1.06 (0.82-1.38) 0.6592 0.664 rs10760151 108 228 133 0.473 0.580 0.82 (0.68-0.98) 0.0293 0.041 rs7036541 108 229 133 0.473 0.644 0.83 (0.69-0.99) 0.0413 0.064 rs12683062 7 93 369 0.114 0.648 1.05 (0.79-1.39) 0.7573 0.849 rs3747843 106 236 127 0.478 0.926 1.17 (0.98-1.40) 0.0834 0.186 rs3736855 106 230 134 0.470 0.711 0.84 (0.70-1.00) 0.0513 0.089 rs10818512 38 183 249 0.276 0.566 1.15 (0.95-1.41) 0.1529 0.130 rs3736856 85 216 167 0.412 0.296 1.16 (0.97-1.39) 0.1168 0.219 rs2057466 39 193 238 0.288 1 1.15 (0.95-1.40) 0.1522 0.195 rs1535655 38 186 245 0.279 0.732 1.12 (0.92-1.37) 0.2466 0.169 rs2146836 37 193 240 0.284 0.910 1.17 (0.96-1.43) 0.1115 0.186 rs2302498 77 216 177 0.394 0.440 1.13 (0.94-1.36) 0.1852 0.178 rs7047038 38 182 242 0.279 0.645 1.12 (0.92-1.37) 0.2598 0.156 rs10760152 38 188 244 0.281 0.820 1.12 (0.92-1.37) 0.2492 0.259 rs10760153 107 229 131 0.474 0.711 0.82 (0.69-0.99) 0.0363 0.059 rs942152 87 221 161 0.421 0.507 1.11 (0.92-1.33) 0.2782 0.296 rs9408928 5 36 429 0.049 0.003 1.16 (0.77-1.73) 0.5026 0.195 rs9409230 4 34 426 0.045 0.010 1.22 (0.80-1.85) 0.3688 0.105 rs7030849 78 216 174 0.397 0.441 1.16 (0.97-1.40) 0.1027 0.088 rs747846 50 176 243 0.294 0.045 1.04 (0.85-1.26) 0.7274 0.910 rs12343027 1 49 420 0.054 1 1.06 (0.71-1.57) 0.7824 0.610 rs4837817 13 110 347 0.145 0.261 0.93 (0.72-1.21) 0.5914 0.858 rs4595204 2 31 436 0.037 0.129 0.93 (0.58-1.52) 0.7864 0.285 rs10985196 18 145 306 0.193 0.882 1.24 (1.00-1.55) 0.0506 0.094 rs306781 1 21 448 0.024 0.241 0.38 (0.18-0.83) 0.0142 0.074 rs11787991 0 37 431 0.040 1 0.80 (0.49-1.30) 0.3633 0.329 rs7046030 17 135 312 0.182 0.640 1.25 (0.99-1.57) 0.0563 0.106 rs12683459 17 140 313 0.185 0.760 1.24 (0.99-1.56) 0.0550 0.106 rs11788156 2 33 435 0.039 0.155 1.05 (0.66-1.66) 0.8301 0.234 rs4837839 122 224 123 0.499 0.356 0.78 (0.65-0.93) 0.0078 0.029 rs306783 81 236 151 0.425 0.570 1.16 (0.97-1.39) 0.1078 0.251 rs306784 58 219 191 0.358 0.763 1.19 (0.98-1.43) 0.0697 0.176 rs10818527 42 205 222 0.308 0.665 1.30 (1.07-1.57) 0.0070 0.026 rs16910509 16 79 375 0.118 1.61E-04 1.13 (0.86-1.48) 0.4142 0.274 rs2304393 1 42 421 0.047 1 0.92 (0.60-1.43) 0.7163 0.938 rs12683989 0 47 423 0.050 0.620 1.11 (0.74-1.66) 0.6148 0.554 rs1560980 1 31 435 0.035 0.443 1.01 (0.62-1.65) 0.9548 0.999 rs7039494 18 108 341 0.154 0.020 1.12 (0.88-1.43) 0.3775 0.091 rs12340264 6 77 386 0.095 0.289 0.93 (0.68-1.27) 0.6657 0.889 rs12554081 19 89 362 0.135 2.00E-04 1.14 (0.88-1.48) 0.3355 0.065 rs17086 69 190 210 0.350 0.019 1.05 (0.87-1.26) 0.6577 0.713 rs10818531 1 42 425 0.047 1 0.92 (0.60-1.42) 0.7092 0.935 rs367395 13 82 375 0.115 0.005 1.16 (0.88-1.53) 0.2945 0.123 ^(a)Positions according to genomic conting NT_008470.18 (Entrez Nucleotide). The minor allele is listed first, followed by the position in National Center for Biotechnology Information Genome Build 36.2 and then the major allele. ^(b)MAF is the minor allele frequency. ^(c)Hardy-Weinberg equilibrium testing was accomplished through the exact test of Weir as described in the Materials and Methods. ^(d)Calculated using Cochran-Armitage Trend test. ^(e)Calculated using William's-corrected G test.

TABLE 6 Minor allele frequencies and allele-based association of chr 9q33 SNPs with RA (SAMPLE SET 2-661 Cases/1322 Controls) Position & Case Genotypes Marker Gene Type Alleles^(a) 11 12 22 MAF^(b) HW^(c) rs10984984 MEGF9 intronic T122503297C rs10760112 MEGF9 intronic C122507391T 62 289 308 0.313 0.652 rs10985014 G122538111A 10 160 489 0.137 0.513 rs7026635 FBXW2 intronic G122589848A 46 272 341 0.276 0.437 rs1577001 LOC intronic T122597128C 1 29 629 0.024 0.303 402377 rs7873274 LOC intronic C122599313T 9 136 513 0.117 1 402377 rs10985044 A122603331G rs10760117 PSMD5 intronic T122626558G 107 342 209 0.422 0.110 rs10739575 G122645922A 14 202 443 0.175 0.135 rs933003 A122647650G 0 32 627 0.024 1 rs10985051 C122647701A 15 167 477 0.149 0.879 rs13291973 T122654694G 7 97 554 0.084 0.212 rs1837 PHF19 3′UTR T122658050C 44 285 330 0.283 0.103 rs1056567 PHF19 S181S T122671866C 65 320 274 0.341 0.046 rs10985070 PHF19 intronic C122675942A rs1953126 T122680321C 87 319 250 0.376 0.405 rs1930777 A122680989G rs1609810 G122682172A 87 325 245 0.380 0.215 rs10985073 T122683676C rs7034390 A122686309T rs10818482 A122687906G rs2270231 C122690803G rs2072438 T122691122C rs881375 T122692719C 88 325 245 0.381 0.247 rs6478486 T122695150C 87 325 246 0.379 0.246 rs1860824 G122699160T rs10760126 T122702439C rs4836834 TRAF1 3′UTR T122705722A 130 345 184 0.459 0.183 rs10435844 TRAF1 intronic G122708020T rs2239657 TRAF1 P340P G122711341A 87 325 247 0.379 0.246 rs12377786 TRAF1 intronic G122711580T rs2239658 TRAF1 intronic T122711658C rs7021880 TRAF1 intronic C122713711G 77 306 275 0.350 0.607 rs3747841 TRAF1 S170S A122715622G 0 14 645 0.011 1 rs2416804 TRAF1 intronic G122716217C rs2416805 TRAF1 intronic T122716303C rs876445 TRAF1 intronic A122716923 T rs10118357 TRAF1 intronic G122719889A rs2269059 TRAF1 intronic A122722293T 4 90 565 0.074 0.776 rs2191959 TRAF1 intronic A122723655 T rs7021049 TRAF1 intronic G122723803T 133 342 184 0.461 0.273 rs7021206 TRAF1 intronic G122723978A rs1014529 TRAF1 intronic C122724764G rs1930781 TRAF1 intronic G122727655A rs1930782 TRAF1 intronic C122727726T rs3761846 C122729418T rs2416806 G122730113C rs7864019 A122732689T rs10760130 G122741811A rs10818488 A122744908G rs2900180 T122746203C 88 325 244 0.381 0.247 rs10760131 G122749962T 0 19 634 0.015 1 rs12004487 C5 intronic C122756502T 5 95 558 0.080 0.595 rs16910233 C5 intronic G122763432C 0 5 654 0.004 1 rs2269066 C5 intronic T122776839C 15 141 503 0.130 0.169 rs2269067 C5 intronic C122776861G 41 212 405 0.223 0.072 rs2159776 C5 intronic C122795981T 134 333 191 0.457 0.638 rs10760134 C5 intronic C122798246T rs7040033 C5 intronic A122798865G 128 339 192 0.451 0.346 rs10760135 C5 intronic T122802827C 132 332 194 0.453 0.694 rs17611 C5 I802V A122809021G 129 336 196 0.4493 0.530 rs10818496 C5 intronic G122814284A 87 286 286 0.349 0.265 rs10985126 C5 G385G C122823755T 34 198 425 0.202 0.091 rs993247 C5 intronic G122825070A rs2416811 C5 intronic T122829455C 128 335 196 0.448 0.529 rs10156396 C5 intronic T122830953C rs10985132 C5 intronic T122835515C rs10818499 C5 intronic A122839915T rs9644911 C5 intronic G122848925A 33 217 409 0.215 0.563 rs10739585 C5 intronic G122849360C rs7871371 T122855883C rs7855998 T122855917C rs7029523 T122857434C rs1924081 A122862268T rs1323472 C122866156G 110 326 222 0.415 0.630 rs7042135 T122876474C rs6478498 A122877723G rs7856420 G122878978C rs10739586 T122881893A rs6478499 A122882694G rs4837808 A122886441G rs12685539 CEP110 intronic G122896746T 0 20 639 0.015 1 rs10760146 CEP110 intronic T122896906C rs9299273 CEP110 intronic T122898251A rs9657673 CEP110 intronic T122900196C 124 328 207 0.437 0.812 rs7022941 CEP110 intronic G122907291C rs1998506 CEP110 intronic G122910284A rs4837809 CEP110 intronic T122913032G rs1407910 CEP110 intronic T122915251C rs2146838 CEP110 intronic G122916126A rs1951784 CEP110 intronic G122916272A rs10818508 CEP110 intronic G122922855A rs10081760 CEP110 intronic A122924127G 56 297 305 0.311 0.202 rs2900185 CEP110 intronic A122927191G rs4837811 CEP110 intronic T122941415G rs2068055 CEP110 intronic T122943988A 15 146 498 0.134 0.310 rs10760151 CEP110 intronic G122945183 A rs7036541 CEP110 intronic G122945456C rs12683062 CEP110 intronic T122946625G 19 111 528 0.113 2.56E-04 rs3747843 CEP110 intronic A122954127G 164 337 158 0.505 0.586 rs3736855 CEP110 V1398V A122956841T 129 325 205 0.442 1 rs10818512 CEP110 intronic A122957176G rs3736856 CEP110 intronic G122960384A 128 318 213 0.436 0.635 rs2057466 CEP110 intronic T122966751C rs1535655 CEP110 intronic G122968390A rs2146836 CEP110 intronic A122970117C rs2302498 CEP110 intronic A122976150T rs7047038 RAB14 intronic T122986768G rs10760152 RAB14 intronic A122987806C 55 293 311 0.306 0.271 rs10760153 RAB14 intronic C122988196T rs942152 RAB14 intronic C122991506T 133 322 204 0.446 0.813 rs9408928 RAB14 intronic C122991738T 5 70 583 0.061 0.084 rs9409230 T123007581A 3 65 589 0.054 0.427 rs7030849 C123009655T 117 326 215 0.426 0.750 rs747846 T123022431G 70 259 330 0.303 0.080 rs12343027 T123027074C 2 50 606 0.041 0.298 rs4837817 C123034984G 14 160 485 0.143 0.873 rs4595204 T123056182A 1 58 599 0.046 1 rs10985196 GSN intronic A123072865C 46 217 396 0.234 0.039 rs306781 GSN intronic C123082765T 0 31 628 0.024 1 rs11787991 GSN intronic T123086454G 2 41 616 0.034 0.171 rs7046030 GSN intronic C123087058T 40 209 408 0.220 0.068 rs12683459 GSN intronic A123088119G 40 211 407 0.221 0.089 rs11788156 GSN intronic C123111661G 2 57 600 0.046 0.644 rs4837839 GSN intronic T123111948C 136 303 220 0.436 0.096 rs306783 GSN intronic T123112418C 142 294 223 0.439 0.018 rs306784 GSN intronic T123112473G 104 292 262 0.380 0.137 rs10818527 GSN intronic A123115075G 94 283 282 0.357 0.107 rs16910509 GSN intronic T123123292C 14 128 516 0.119 0.090 rs2304393 GSN G471G T123123435C 0 48 611 0.036 1 rs12683989 GSN intronic T123125867C 2 94 563 0.074 0.568 rs1560980 GSN intronic C123133818G 3 47 609 0.040 0.081 rs7039494 GSN intronic T123134411A 15 164 480 0.147 0.758 rs12340264 STOM intronic T123149742C 8 108 543 0.094 0.355 rs12554081 STOM intronic A123165145C 18 150 491 0.141 0.145 rs17086 STOM intronic G123165341A rs10818531 STOM intronic T123168845C 1 48 609 0.038 1 rs367395 STOM intronic T123171333G 11 131 517 0.116 0.445 Control Genotypes Genotypic Marker 11 12 22 MAF HW^(c) OR (95% CI) P^(d) P^(e) rs10984984 rs10760112 105 572 639 0.297 0.147 1.08 (0.94-1.25) 0.2866 0.507 rs10985014 22 325 969 0.140 0.424 0.97 (0.80-1.18) 0.7527 0.944 rs7026635 67 505 745 0.243 0.133 1.19 (1.03-1.38) 0.0197 0.065 rs1577001 0 54 1263 0.021 1 1.15 (0.74-1.80) 0.5377 0.412 rs7873274 16 239 1058 0.103 0.550 1.15 (0.93-1.42) 0.1894 0.404 rs10985044 rs10760117 195 649 474 0.394 0.273 1.12 (0.98-1.29) 0.0805 0.171 rs10739575 25 349 942 0.152 0.285 1.18 (0.99-1.41) 0.0580 0.141 rs933003 0 56 1260 0.021 1 1.14 (0.74-1.78) 0.5419 0.546 rs10985051 24 347 946 0.150 0.279 1.00 (0.83-1.20) 0.9521 0.729 rs13291973 9 200 1107 0.083 1 1.02 (0.80-1.30) 0.8704 0.672 rs1837 72 514 731 0.250 0.142 1.19 (1.02-1.38) 0.0216 0.067 rs1056567 104 571 641 0.296 0.146 1.23 (1.07-1.42) 0.0028 0.009 rs10985070 rs1953126 125 561 632 0.308 1 1.35 (1.18-1.56) 1.69E−05 7.83E−05 rs1930777 rs1609810 125 558 633 0.307 0.897 1.38 (1.20-1.59) 4.21E−06 1.55E−05 rs10985073 rs7034390 rs10818482 rs2270231 rs2072438 rs881375 125 561 629 0.308 1 1.38 (1.20-1.58) 4.78E−06 1.99E−05 rs6478486 124 558 631 0.307 1 1.38 (1.20-1.58) 4.83E−06 1.90E−05 rs1860824 rs10760126 rs4836834 205 631 481 0.395 0.954 1.30 (1.14-1.48) 1.10E−04 3.26E−04 rs10435844 rs2239657 125 557 635 0.306 0.846 1.38 (1.20-1.58) 4.86E−06 1.78E−05 rs12377786 rs2239658 rs7021880 100 516 701 0.272 0.728 1.44 (1.25-1.66) 5.09E−07 3.09E−06 rs3747841 0 37 1279 0.014 1 0.75 (0.41-1.40) 0.3640 0.359 rs2416804 rs2416805 rs876445 rs10118357 rs2269059 7 196 1114 0.080 0.850 0.93 (0.72-1.19) 0.5511 0.757 rs2191959 rs7021049 204 630 483 0.394 1 1.32 (1.15-1.50) 4.78E−05 1.79E−04 rs7021206 rs1014529 rs1930781 rs1930782 rs3761846 rs2416806 rs7864019 rs10760130 rs10818488 rs2900180 126 558 633 0.308 0.846 1.39 (1.21-1.59) 3.21E−06 1.19E−05 rs10760131 1 56 1242 0.022 0.478 0.65 (0.38-1.09) 0.1003 0.286 rs12004487 8 220 1089 0.090 0.498 0.88 (0.69-1.12) 0.2981 0.410 rs16910233 0 21 1295 0.008 1 0.47 (0.18-1.26) 0.1238 0.111 rs2269066 12 209 1096 0.088 0.497 1.54 (1.25-1.89) 7.19E−05 4.63E−04 rs2269067 35 379 903 0.170 0.560 1.40 (1.19-1.65) 7.10E−05 9.41E−05 rs2159776 261 642 414 0.442 0.696 1.06 (0.93-1.21) 0.3790 0.547 rs10760134 rs7040033 308 640 368 0.477 0.377 0.90 (0.79-1.03) 0.1269 0.127 rs10760135 261 637 418 0.440 0.538 1.05 (0.92-1.20) 0.4562 0.570 rs17611 305 646 371 0.475 0.473 0.90 (0.79-1.03) 0.1269 0.190 rs10818496 184 612 521 0.372 0.860 0.90 (0.79-1.04) 0.1597 0.263 rs10985126 27 362 928 0.158 0.255 1.35 (1.14-1.60) 5.15E−04 3.28E−04 rs993247 rs2416811 302 642 373 0.473 0.439 0.91 (0.79-1.03) 0.1444 0.200 rs10156396 rs10985132 rs10818499 rs9644911 64 446 807 0.218 0.809 0.98 (0.84-1.15) 0.8186 0.915 rs10739585 rs7871371 rs7855998 rs7029523 rs1924081 rs1323472 190 606 521 0.374 0.518 1.19 (1.04-1.36) 0.0140 0.036 rs7042135 rs6478498 rs7856420 rs10739586 rs6478499 rs4837808 rs12685539 0 25 1291 0.009 1 1.61 (0.89-2.90) 0.1109 0.121 rs10760146 rs9299273 rs9657673 277 647 393 0.456 0.739 0.93 (0.81-1.06) 0.2600 0.480 rs7022941 rs1998506 rs4837809 rs1407910 rs2146838 rs1951784 rs10818508 rs10081760 119 519 676 0.288 0.179 1.11 (0.96-1.29) 0.1413 0.056 rs2900185 rs4837811 rs2068055 24 356 934 0.154 0.167 0.85 (0.70-1.03) 0.0887 0.052 rs10760151 rs7036541 rs12683062 11 236 1070 0.098 0.755 1.18 (0.95-1.46) 0.1463 0.003 rs3747843 321 640 355 0.487 0.348 1.07 (0.94-1.22) 0.3029 0.343 rs3736855 256 611 370 0.454 0.909 0.95 (0.83-1.09) 0.4953 0.791 rs10818512 rs3736856 236 638 443 0.421 0.821 1.06 (0.93-1.21) 0.4007 0.682 rs2057466 rs1535655 rs2146836 rs2302498 rs7047038 rs10760152 110 506 701 0.276 0.168 1.16 (1.00-1.34) 0.0490 0.029 rs10760153 rs942152 204 626 485 0.393 0.954 1.24 (1.09-1.42) 0.0015 0.006 rs9408928 7 112 1198 0.048 0.026 1.29 (0.97-1.72) 0.0949 0.261 rs9409230 8 101 1207 0.044 0.003 1.23 (0.91-1.66) 0.1986 0.245 rs7030849 186 588 462 0.388 1 1.17 (1.02-1.34) 0.0259 0.082 rs747846 180 575 562 0.355 0.092 0.79 (0.68-0.91) 0.0014 0.005 rs12343027 3 113 1201 0.045 0.746 0.90 (0.65-1.26) 0.5514 0.734 rs4837817 35 347 935 0.158 0.679 0.88 (0.73-1.07) 0.1993 0.437 rs4595204 0 120 1197 0.046 0.108 1.00 (0.73-1.37) 0.9616 0.420 rs10985196 35 363 919 0.164 1 1.56 (1.32-1.83) 1.79E−07 4.93E−07 rs306781 0 65 1252 0.025 1 0.95 (0.62-1.47) 0.8211 0.822 rs11787991 1 76 1239 0.030 1 1.16 (0.80-1.68) 0.4460 0.494 rs7046030 34 342 942 0.156 0.675 1.53 (1.29-1.81) 9.85E-07 5.14E-06 rs12683459 32 344 939 0.155 0.916 1.55 (1.31-1.83) 4.86E-07 2.19E-06 rs11788156 2 100 1214 0.040 1 1.18 (0.85-1.63) 0.3177 0.588 rs4837839 263 641 412 0.443 0.655 0.97 (0.85-1.11) 0.6753 0.505 rs306783 249 612 455 0.422 0.090 1.07 (0.94-1.22) 0.3286 0.383 rs306784 178 595 544 0.361 0.473 1.08 (0.95-1.24) 0.2536 0.390 rs10818527 126 581 610 0.316 0.484 1.20 (1.05-1.38) 0.0100 0.008 rs16910509 25 350 942 0.152 0.285 0.75 (0.62-0.92) 0.0045 0.002 rs2304393 1 120 1195 0.046 0.523 0.78 (0.55-1.09) 0.1402 0.342 rs12683989 5 116 1196 0.048 0.218 1.60 (1.22-2.10) 7.02E−04 0.002 rs1560980 3 103 1210 0.041 0.487 0.97 (0.69-1.36) 0.8590 0.622 rs7039494 44 410 863 0.189 0.653 0.74 (0.62-0.89) 0.0011 0.004 rs12340264 17 235 1064 0.102 0.296 0.91 (0.73-1.14) 0.4284 0.708 rs12554081 34 381 902 0.170 0.437 0.80 (0.66-0.96) 0.0181 0.013 rs17086 rs10818531 1 122 1194 0.047 0.360 0.80 (0.57-1.12) 0.1849 0.345 rs367395 25 340 949 0.148 0.445 0.75 (0.62-0.92) 0.0053 0.010 ^(a)Positions according to genomic conting NT_008470.18 (Entrez Nucleotide). The minor allele is listed first, followed by the position in National Center for Biotechnology Information Genome Build 36.2 and then the major allele. ^(b)MAF is the minor allele frequency. ^(c)Hardy-Weinberg equilibrium testing was accomplished through the exact test of Weir as described in the Materials and Methods. ^(d)Calculated using Cochran-Armitage Trend test. ^(e)Calculated using William's-corrected G test.

TABLE 7 Minor allele frequencies and allele-based association of chr 9q33 SNPs with RA-SAMPLE SET 3 (596 Cases/705 Controls) Position & Case Genotypes Marker Gene Type Alleles^(a) 11 12 22 MAF^(b) HW^(c) rs10984984 MEGF9 intronic T122503297C rs10760112 MEGF9 intronic C122507391T 57 247 284 0.307 0.771 rs10985014 G122538111A rs7026635 FBXW2 intronic G122589848A 54 233 301 0.290 0.368 rs1577001 LOC402377 intronic T122597128C rs7873274 LOC402377 intronic C122599313T rs10985044 A122603331G rs10760117 PSMD5 intronic T122626558G 115 292 180 0.445 0.933 rs10739575 G122645922A 21 170 399 0.180 0.577 rs933003 A122647650G 0 33 558 0.028 1 rs10985051 C122647701A rs13291973 T122654694G rs1837 PHF19 3′UTR T122658050C 54 239 296 0.295 0.553 rs1056567 PHF19 S181S T122671866C 74 271 245 0.355 1 rs10985070 PHF19 intronic C122675942A rs1953126 T122680321C 83 287 221 0.3832 0.543 rs1930777 A122680989G rs1609810 G122682172A 84 281 223 0.382 0.794 rs10985073 T122683676C rs7034390 A122686309T rs10818482 A122687906G rs2270231 C122690803G rs2072438 T122691122C rs881375 T122692719C 86 278 223 0.383 1 rs6478486 T122695150C 85 276 224 0.381 1 rs1860824 G122699160T rs10760126 T122702439C rs4836834 TRAF1 3′UTR T122705722A 137 301 151 0.488 0.621 rs10435844 TRAF1 intronic G122708020T rs2239657 TRAF1 P340P G122711341A 85 282 224 0.382 0.862 rs12377786 TRAF1 intronic G122711580T rs2239658 TRAF1 intronic T122711658C rs7021880 TRAF1 intronic C122713711G 78 274 238 0.364 1 rs3747841 TRAF1 S170S A122715622G rs2416804 TRAF1 intronic G122716217C rs2416805 TRAF1 intronic T122716303C rs876445 TRAF1 intronic A122716923 T rs10118357 TRAF1 intronic G122719889A rs2269059 TRAF1 intronic A122722293 T rs2191959 TRAF1 intronic A122723655 T rs7021049 TRAF1 intronic G122723803T 138 299 154 0.486 0.805 rs7021206 TRAF1 intronic G122723978A rs1014529 TRAF1 intronic C122724764G rs1930781 TRAF1 intronic G122727655A rs1930782 TRAF1 intronic C122727726T rs3761846 C122729418T rs2416806 G122730113C rs7864019 A122732689T rs10760130 G122741811A rs10818488 A122744908G rs2900180 T122746203C 88 283 219 0.389 0.863 rs10760131 G122749962T rs12004487 C5 intronic C122756502T rs16910233 C5 intronic G122763432C rs2269066 C5 intronic T122776839C 10 115 465 0.114 0.314 rs2269067 C5 intronic C122776861G 33 215 343 0.238 1 rs2159776 C5 intronic C122795981T 134 285 170 0.469 0.508 rs10760134 C5 intronic C122798246T rs7040033 C5 intronic A122798865G 101 284 205 0.412 0.865 rs10760135 C5 intronic T122802827C rs17611 C5 I802V A122809021G 102 275 209 0.409 0.494 rs10818496 C5 intronic G122814284A rs10985126 C5 G385G C122823755T 26 204 359 0.217 0.717 rs993247 C5 intronic G122825070A rs2416811 C5 intronic T122829455C 101 279 210 0.408 0.610 rs10156396 C5 intronic T122830953C rs10985132 C5 intronic T122835515C rs10818499 C5 intronic A122839915T rs9644911 C5 intronic G122848925A rs10739585 C5 intronic G122849360C rs7871371 T122855883C rs7855998 T122855917C rs7029523 T122857434C rs1924081 A122862268T rs1323472 C122866156G 122 292 176 0.454 1 rs7042135 T122876474C rs6478498 A122877723G rs7856420 G122878978C rs10739586 T122881893A rs6478499 A122882694G rs4837808 A122886441G rs12685539 CEP110 intronic G122896746T rs10760146 CEP110 intronic T122896906C rs9299273 CEP110 intronic T122898251A rs9657673 CEP110 intronic T122900196C 98 280 213 0.403 0.732 rs7022941 CEP110 intronic G122907291C rs1998506 CEP110 intronic G122910284A rs4837809 CEP110 intronic T122913032G rs1407910 CEP110 intronic T122915251C rs2146838 CEP110 intronic G122916126A rs1951784 CEP110 intronic G122916272A rs10818508 CEP110 intronic G122922855A rs10081760 CEP110 intronic A122924127G 67 263 261 0.336 1 rs2900185 CEP110 intronic A122927191G rs4837811 CEP110 intronic T122941415G rs2068055 CEP110 intronic T122943988A rs10760151 CEP110 intronic G122945183A rs7036541 CEP110 intronic G122945456C rs12683062 CEP110 intronic T122946625G 11 128 451 0.127 0.577 rs3747843 CEP110 intronic A122954127G 170 281 139 0.5263 0.283 rs3736855 CEP110 V1398V A122956841T 102 276 212 0.407 0.444 rs10818512 CEP110 intronic A122957176G rs3736856 CEP110 intronic G122960384A rs2057466 CEP110 intronic T122966751C rs1535655 CEP110 intronic G122968390A rs2146836 CEP110 intronic A122970117C rs2302498 CEP110 intronic A122976150T rs7047038 RAB14 intronic T122986768G rs10760152 RAB14 intronic A122987806C 63 259 269 0.326 1 rs10760153 RAB14 intronic C122988196T rs942152 RAB14 intronic C122991506T 141 293 157 0.486 0.869 rs9408928 RAB14 intronic C122991738T 0 68 522 0.058 0.248 rs9409230 T123007581A 0 60 530 0.051 0.390 rs7030849 C123009655T 129 287 173 0.463 0.620 rs747846 T123022431G rs12343027 T123027074C rs4837817 C123034984G rs4595204 T123056182A rs10985196 GSN intronic A123072865C 35 205 351 0.233 0.490 rs306781 GSN intronic C123082765T 0 14 577 0.012 1 rs11787991 GSN intronic T123086454G rs7046030 GSN intronic C123087058T 32 195 363 0.219 0.400 rs12683459 GSN intronic A123088119G 32 193 366 0.217 0.334 rs11788156 GSN intronic C123111661G rs4837839 GSN intronic T123111948C 114 263 214 0.415 0.042 rs306783 GSN intronic T123112418C 131 276 184 0.455 0.159 rs306784 GSN intronic T123112473G 98 270 223 0.394 0.302 rs10818527 GSN intronic A123115075G 83 267 241 0.366 0.535 rs16910509 GSN intronic T123123292C rs2304393 GSN G471G T123123435C rs12683989 GSN intronic T123125867C 2 67 522 0.060 1 rs1560980 GSN intronic C123133818G rs7039494 GSN intronic T123134411A rs12340264 STOM intronic T123149742C rs12554081 STOM intronic A123165145C rs17086 STOM intronic G123165341A rs10818531 STOM intronic T123168845C rs367395 STOM intronic T123171333G Control Genotypes Genotypic Marker 11 12 22 MAFb HW^(c) OR (95% CI) P^(d) P^(e) rs10984984 rs10760112 71 283 346 0.304 0.246 1.02 (0.86-1.20) 0.8532 0.843 rs10985014 rs7026635 45 268 387 0.256 0.921 1.19 (1.00-1.41) 0.0534 0.118 rs1577001 rs7873274 rs10985044 rs10760117 124 319 253 0.407 0.182 1.16 (1.00-1.36) 0.0599 0.099 rs10739575 23 189 488 0.168 0.347 1.09 (0.89-1.33) 0.4365 0.724 rs933003 0 49 651 0.035 1 0.79 (0.51-1.24) 0.2986 0.298 rs10985051 rs13291973 rs1837 45 271 383 0.258 0.843 1.20 (1.01-1.43) 0.0402 0.101 rs1056567 74 300 326 0.320 0.728 1.17 (0.99-1.38) 0.0612 0.165 rs10985070 rs1953126 82 322 293 0.349 0.677 1.16 (0.99-1.36) 0.0661 0.183 rs1930777 rs1609810 82 320 297 0.346 0.802 1.17 (0.99-1.37) 0.0600 0.171 rs10985073 rs7034390 rs10818482 rs2270231 rs2072438 rs881375 85 320 294 0.351 0.934 1.15 (0.98-1.35) 0.0849 0.227 rs6478486 81 320 297 0.345 0.738 1.17 (0.99-1.37) 0.0585 0.162 rs1860824 rs10760126 rs4836834 136 332 232 0.431 0.397 1.26 (1.08-1.47) 0.0042 0.010 rs10435844 rs2239657 82 320 298 0.346 0.803 1.17 (1.00-1.38) 0.0523 0.153 rs12377786 rs2239658 rs7021880 79 309 312 0.334 0.865 1.15 (0.97-1.35) 0.1020 0.259 rs3747841 rs2416804 rs2416805 rs876445 rs10118357 rs2269059 rs2191959 rs7021049 137 331 232 0.432 0.355 1.24 (1.07-1.45) 0.0062 0.016 rs7021206 rs1014529 rs1930781 rs1930782 rs3761846 rs2416806 rs7864019 rs10760130 rs10818488 rs2900180 85 323 292 0.352 0.804 1.17 (1.00-1.37) 0.0523 0.153 rs10760131 rs12004487 rs16910233 rs2269066 7 141 552 0.111 0.701 1.04 (0.81-1.33) 0.7678 0.544 rs2269067 25 231 444 0.201 0.555 1.24 (1.03-1.50) 0.0222 0.066 rs2159776 133 375 192 0.458 0.040 1.05 (0.90-1.22) 0.5509 0.130 rs10760134 rs7040033 139 350 209 0.450 0.760 0.86 (0.73-1.00) 0.0521 0.143 rs10760135 rs17611 145 341 213 0.451 0.703 0.84 (0.72-0.98) 0.0316 0.096 rs10818496 rs10985126 30 205 465 0.189 0.219 1.19 (0.98-1.44) 0.0799 0.113 rs993247 rs2416811 138 351 211 0.448 0.760 0.85 (0.73-0.99) 0.0401 0.100 rs10156396 rs10985132 rs10818499 rs9644911 rs10739585 rs7871371 rs7855998 rs7029523 rs1924081 rs1323472 118 321 261 0.398 0.269 1.26 (1.08-1.47) 0.0044 0.013 rs7042135 rs6478498 rs7856420 rs10739586 rs6478499 rs4837808 rs12685539 rs10760146 rs9299273 rs9657673 134 342 224 0.436 0.878 0.87 (0.75-1.02) 0.0924 0.240 rs7022941 rs1998506 rs4837809 rs1407910 rs2146838 rs1951784 rs10818508 rs10081760 62 303 332 0.306 0.593 1.15 (0.97-1.35) 0.1072 0.246 rs2900185 rs4837811 rs2068055 rs10760151 rs7036541 rs12683062 10 131 559 0.108 0.433 1.20 (0.95-1.53) 0.1339 0.327 rs3747843 180 342 178 0.501 0.546 1.10 (0.95-1.29) 0.2160 0.431 rs3736855 140 340 220 0.443 0.702 0.86 (0.74-1.01) 0.0681 0.182 rs10818512 rs3736856 rs2057466 rs1535655 rs2146836 rs2302498 rs7047038 rs10760152 51 307 342 0.292 0.121 1.17 (0.99-1.38) 0.0681 0.088 rs10760153 rs942152 137 330 232 0.432 0.317 1.25 (1.07-1.45) 0.0064 0.021 rs9408928 0 84 616 0.060 0.166 0.96 (0.69-1.33) 0.7920 0.792 rs9409230 1 70 629 0.051 1 0.99 (0.70-1.40) 0.9379 0.612 rs7030849 130 321 249 0.415 0.140 1.21 (1.04-1.42) 0.0173 0.048 rs747846 rs12343027 rs4837817 rs4595204 rs10985196 32 239 429 0.216 0.912 1.10 (0.91-1.32) 0.3268 0.513 rs306781 1 11 688 0.009 0.055 1.28 (0.60-2.73) 0.5371 0.404 rs11787991 rs7046030 25 227 445 0.199 0.634 1.13 (0.94-1.37) 0.1970 0.258 rs12683459 25 229 446 0.199 0.555 1.12 (0.92-1.35) 0.2590 0.272 rs11788156 rs4837839 149 329 222 0.448 0.194 0.88 (0.75-1.02) 0.1082 0.226 rs306783 136 341 223 0.438 0.818 1.07 (0.92-1.25) 0.3858 0.477 rs306784 87 334 279 0.363 0.415 1.14 (0.97-1.34) 0.1018 0.106 rs10818527 81 320 299 0.344 0.802 1.10 (0.94-1.29) 0.2448 0.399 rs16910509 rs2304393 rs12683989 0 83 614 0.060 0.163 1.01 (0.73-1.40) 0.9442 0.241 rs1560980 rs7039494 rs12340264 rs12554081 rs17086 rs10818531 rs367395 aPositions according to genomic conting NT_008470.18 (Entrez Nucleotide). The minor allele is listed first, followed by the position in National Center for Biotechnology Information Genome Build 36.2 and then the major allele. ^(b)MAF is the minor allele frequency. ^(c)Hardy-Weinberg equilibrium testing was accomplished through the exact test of Weir as described in the Materials and Methods. ^(d)Calculated using Cochran-Armitage Trend test. ^(c)Calculated using William's-corrected G test.

TABLE 8 Demographic and clinical information Sample Set Subphenotype 1^(a) 2^(b) 3^(c) Genetic background White (North American) White (North American) White (Dutch) No. of cases 475  661 596 No. of controls 475 1322 705 Female:male 314:161 536:125 362:196^(d) Average age of onset (years) 46.97 ± 11.83 38.61 ± 13.61 54.58^(e) ± 13.38 % RF-positive 100% 82% 72%^(f) ^(a)All 950 samples were genotyped for a single SNP, rs10818488, in the candidate gene study performed by Kurreeman et al [35]. ^(b)475 patient samples were included in the initial whole genome association study performed by Plenge et al [34]. ^(c)436 patients and 94 controls samples were included in the candidate gene study performed by Kurreeman et al [35]. ^(d)Information on gender was available for 558 patients. ^(e)Information on age of onset was available for 306 patients. ^(f)Information on RF status was available for 440 patients.

TABLE 9 Combined analysis of 43 chr 9q33.2 SNPs genotyped in all three RA sample sets Combined Analysis Position & OR_(common) Trend Genotypic Marker Gene Type Alleles^(a) (95% CI)^(b) P_(comb) ^(c) P_(comb)c rs10760112 MEGF9 intronic C122507391T 1.17 (1.02-1.23) 0.035 0.136 rs7026635 FBXW2 intronic G122589848A 1.24 (1.10-1.35) 0.001 0.012 rs10760117 PSMD5 intronic T122626558G 1.26 (1.10-1.31) 2.79E−04 0.003 rs10739575 G122645922A 1.16 (1.03-1.30) 0.081 0.349 rs933003 A122647650G 1.12 (0.79-1.40) 0.255 0.243 rs1837 PHF19 3′UTR T122658050C 1.28 (1.12-1.36) 2.17E−04 0.002 rs1056567 PHF19 S181S T122671866C 1.25 (1.12-1.35) 1.11E−04 0.002 rs1953126 T122680321C 1.28 (1.16-1.40) 1.45E−06 4.24E−05 rs1609810 G122682172A 1.29 (1.19-1.42) 1.92E−07 5.24E−06 rs881375 T122692719C 1.27 (1.17-1.41) 4.69E−07 1.09E−05 rs6478486 T122695150C 1.29 (1.19-1.42) 1.35E−07 3.75E−06 rs4836834 TRAF1 3′UTR T122705722A 1.32 (1.19-1.43) 8.13E−08 1.84E−06 rs2239657 TRAF1 P340P G122711341A 1.29 (1.19-1.43) 1.49E−07 3.89E−06 rs7021880 TRAF1 intronic C122713711G 1.33 (1.21-1.46) 5.41E−09 2.27E−07 rs7021049 TRAF1 intronic G122723803T 1.32 (1.20-1.43) 4.09E−08 1.22E−06 rs2900180 T122746203C 1.27 (1.18-1.41) 3.32E−07 7.62E−06 rs2269066 C5 intronic T122776839C 1.29 (1.14-1.53) 1.68E−04 0.001 rs2269067 C5 intronic C122776861G 1.27 (1.17-1.46) 1.71E−05 1.04E−04 rs2159776 C5 intronic C122795981T 1.11 (0.99-1.19) 0.190 0.135 rs7040033 C5 intronic A122798865G 0.86 (0.80-0.96) 0.018 0.060 rs17611 C5 I802V A122809021G 0.84 (0.79-0.94) 0.006 0.040 rs10985126 C5 G385G C122823755T 1.20 (1.11-1.39) 8.69E−04 0.001 rs2416811 C5 intronic T122829455C 0.85 (0.79-0.95) 0.008 0.023 rs1323472 C122866156G 1.23 (1.12-1.34) 1.57E−04 7.06E−04 rs9657673 CEP110 intronic T122900196C 0.86 (0.81-0.96) 0.019 0.052 rs10081760 CEP110 intronic A122924127G 1.15 (1.03-1.25) 0.049 0.066 rs12683062 CEP110 intronic T122946625G 1.12 (1.00-1.33) 0.209 0.029 rs3747843 CEP110 intronic A122954127G 1.13 (1.01-1.21) 0.108 0.304 rs3736855 CEP110 V1398V A122956841T 0.87 (0.82-0.98) 0.048 0.191 rs10760152 RAB14 intronic A122987806C 1.15 (1.05-1.27) 0.028 0.024 rs942152 RAB14 intronic C122991506T 1.18 (1.11-1.32) 2.53E−04 0.002 rs9408928 RAB14 intronic C122991738T 1.11 (0.93-1.38) 0.364 0.378 rs9409230 T123007581A 1.14 (0.93-1.40) 0.499 0.217 rs7030849 C123009655T 1.18 (1.08-1.29) 0.003 0.014 rs10985196 GSN intronic A123072865C 1.25 (1.18-1.46) 6.33E−07 4.12E−06 rs306781 GSN intronic C123082765T 0.68 (0.59-1.16) 0.119 0.284 rs7046030 GSN intronic C123087058T 1.26 (1.18-1.47) 2.05E−06 1.99E−05 rs12683459 GSN intronic A123088119G 1.25 (1.18-1.47) 1.36E−06 9.79E−06 rs4837839 GSN intronic T123111948C 0.85 (0.82-0.97) 0.021 0.076 rs306783 GSN intronic T123112418C 1.11 (1.00-1.19) 0.198 0.405 rs306784 GSN intronic T123112473G 1.15 (1.03-1.24) 0.049 0.131 rs10818527 GSN intronic A123115075G 1.21 (1.08-1.31) 0.001 0.004 rs12683989 GSN intronic T123125867C 1.17 (1.05-1.50) 0.016 0.010 ^(a)Positions according to genomic contig NT_008470.18 (Entrez Nucleotide). The minor allele is listed first, followed by the position in National Center for Biotechnology Information Genome Build 36.2 and then the major allele. ^(b)Calculated for the minor allele using a Mantel-Haenszel common OR. ^(c)Calculated using Fisher's combined test.

TABLE 10 Three-SNP haplotypes for LD Block 1 Sample Set 1 Sample Set 2 Global P = 6.00E−04^(a) Global P = 3.77E−05^(a) No. (Frequency) in No. (Frequency) in Haplotype^(c) Case Control P OR Case Control P OR AGT 507(0.539) 582(0.619) 5.08E-04 0.72 708(0.537) 1595(0.605) 4.01E-05 0.76 GCG 326(0.347) 253(0.269) 2.13E-04 1.44 457(0.347)  714(0.271) 8.71E-07 1.43 AGG  85(0.090)  71(0.075) 0.250 1.22 108(0.082)  232(0.088) 0.540 0.93 GGG  22(0.023)  32(0.034) 0.168 0.68  41(0.031)  92(0.035) 0.539 0.89 Other 0  2(0.002)  4(0.003)   3(0.001) Sample Set 3 Combined Global P = 0.033^(a) Global P_(comb) ^(b) = 1.81E−07 No. (Frequency) in OR_(common) Haplotype^(c) Case Control P OR P_(comb) ^(b) (95% CI)^(d) AGT 604(0.512) 794(0.567) 0.005 0.8 3.08E−08 0.76(0.70-0.83) GCG 425(0.360) 465(0.332) 0.133 1.13 8.00E−09 1.32(1.21-1.45) AGG 122(0.103) 120(0.086) 0.127 1.22 NC 1.09(0.93-1.27) GGG  25(0.021)  20(0.014) 0.135 1.49 NC 0.93(0.70-1.21) Other  5(0.004)  1(0.001) ^(a)The Haplo.Stats package was used to test for association between haplotypes and disease status. ^(b)Calculated for haplotypes with the same effect (risk or protection) in all three sample sets, with use of Fisher's combined test. ^(c)These haplotypes consist of the following SNPs: rs2239657, rs7021880, and rs7021049, respectively.

TABLE 11 Diplotype Analysis for the TRAF1-region SNPs rs2239657, rs7021880 and rs7021049 Sample Set 1 Sample Set 2 Global^(a) P = 0.0069 Global^(a) P = 1.3E−04 No. (Frequency) in No. (Frequency) in Diplotype^(c) Case Control P^(d) OR Case Control P^(d) OR AGT/AGT 140(0.297) 180(0.383) 0.006 0.68 183(0.278) 482(0.366) 8.21E−05 0.67 AGT/Other  51(0.108)  64(0.136) 0.197 0.77  86(0.131) 204(0.155) 0.157 0.82 AGT/GCG 178(0.377) 158(0.336) 0.197 1.20 255(0.387) 426(0.324) 0.006 1.32 GCG/GCG  51(0.108)  34(0.072) 0.068 1.55  76(0.115) 100(0.076) 0.004 1.59 GCG/Other  46(0.098)  27(0.057) 0.028 1.77  50(0.076)  87(0.066) 0.452 1.16 Other/Other  6(0.013)  7(0.015) 0.789 0.85  9(0.014)  18(0.014) 1.000 1.00 Sample Set 3 Combined Analysis Global^(a) P = 0.058 Global^(b) P_(comb) = 8.22E−06 No. (Frequency) in OR_(common) ^(f) Diplotype^(c) Case Control P^(d) OR P_(comb) ^(e) (95% CI) AGT/AGT 153(0.259) 232(0.331) 0.005 0.7  5.35E−07 0.68(0.59-0.78) AGT/Other  81(0.137)  73(0.104) 0.085 1.36 NC 0.94(0.78-1.13) AGT/GCG 218(0.369) 257(0.367) 0.954 1.01 0.035 1.18(1.04-1.34) GCG/GCG  77(0.130)  78(0.111) 0.304 1.19 0.005 1.42(1.16-1.75) GCG/Other  54(0.091)  52(0.074) 0.309 1.25 0.086 1.32(1.04-1.66) Other/Other  8(0.014)  8(0.011) 0.804 1.19 NC 1.01(0.56-1.72) ^(a)Calculated using a Williams-corrected G test. ^(b)Calculated using Fisher's combined test. ^(c)Allele 1 rs2239657-allele 1 rs7021880-allele 1 rs7021049/allele 2 rs2239657-allele 2 rs7021880-allele 2 rs7021049. ^(d)P-values calculated using Fisher's exact test. ^(e)Calculated for diplotypes with the same effect (risk or protection) in all three sample sets, with use of Fisher's combined test. ^(f)Mantel-Haenszel common odds ratio with confidence intervals from Monte Carlo simulation.

TABLE 12 Genotype counts of rs2239657, rs7021880 and rs7021049 stratified by the presence of rheumatoid factor rs2239657 rs7021880 Genotypes Genotypes GG GA AA MAF P^(a) OR_(Allelic) CC CG GG MAF P^(a) OR_(Allelic) Sample Set l^(b) RF-positive cases 62 224 184 0.370 0.008 1.35 (1.11-1.63) 51 225 195 0.347 0.001 1.43 (1.17-1.74) controls 45 195 229 0.304 34 187 249 0.271 Sample Set 2 RF-positive cases 68 268 206 0.373 5.60E−04 1.32 (1.14-1.55) 62 250 229 0.346 2.39E−04 1.27 (1.08-1.49) matched controls 106 457 520 0.309 87 425 571 0.277 RF-negative cases 19 57 41 0.406 0.013 1.63 (1.18-2.27) 15 56 46 0.368 0.005 1.74 (1.24-2.44) matched controls 19 100 115 0.295 13 91 130 0.250 Breslow-Day^(c) 0.263 0.222 Sample Set 3 RF-positive cases 47 156 111 0.398 0.07 1.25 (1.03-1.52) 42 151 121 0.374 0.184 1.19 (0.98-1.45) RF-negative cases 13 63 46 0.364 0.483 1.09 (0.82-1.44) 12 63 47 0.357 0.312 1.11 (0.83-1.47) Controls 82 320 298 0.346 79 309 312 0.334 Monte Carlo^(d) 0.218 0.645 Combined RF-positive cases^(e) 4.02E−05 7.10E−06 RF-negative cases^(f) 0.038 0.013 rs7021049 Genotypes GG GT TT MAF P^(a) OR_(Allelic) Sample Set l^(b) RF-positive cases 103 229 140 0.461 0.002 1.39 (1.16-1.67) controls 68 222 180 0.381 Sample Set 2 RF-positive cases 107 283 152 0.458 8.77E−04 1.30 (1.12-1.50) matched controls 175 505 403 0.395 RF-negative cases 26 59 32 0.474 0.054 1.41 (1.02-1.93) matched controls 29 125 80 0.391 Breslow-Day^(c) 0.656 Sample Set 3 RF-positive cases 73 164 77 0.494 0.019 1.28 (1.06-1.55) RF-negative cases 21 67 34 0.447 0.297 1.06 (0.81-1.39) Controls 137 331 232 0.432 Monte Carlo^(d) 0.116 Combined RF-positive cases^(e) 5.68E−06 RF-negative cases^(f) 0.082 ^(a)Genotypic P-values were calculated except where indicated. ^(b)All cases in this study were RF-positive. ^(c)Differental effects between RF-positive and RF-negative association were determined for sample set 2 using a Breslow-Day test (cases and controls were individually matched). ^(d)Differential effects between RF-positive and RF-negative association were determined for sample set 3 using a Monte Carlo simulation (cases and controls were not individually matched). ^(e)Includes all three sample sets. ^(f)Includes sample sets 2 and 3.

TABLE 13 Pairwise logistic regression analysis of the 27 chr9q33.2 SNPs P adjusted for r² with P adjusted for rs7021049 & Group^(a) Marker rs7021049^(b) P^(c) rs7021049 rs10985196 3 rs10760112 0.157 0.357 0.285 0.770 4 rs10760117 0.329 0.011 0.760 0.579 5 rs10739575 0.086 0.055 0.580 0.893 6 rs933003 0.011 0.757 0.420 0.448 7 rs1837, rs7026635 0.151 0.002 0.169 0.126 8 rs1056567 0.243 5.22E−04 0.200 0.208 1 rs2239657, rs1953126, rs1609810, rs881375, rs6478486, rs2900180 0.685 2.52E−06 0.217 0.254 9 rs7021880 0.607 1.39E−06 0.104 0.072 2 rs7021049, rs4836834 1 1.24E−06 — — 10 rs2269066 0.114 0.002 0.115 0.094 11 rs2269067 0.261 7.64E−06 0.023 0.175 12 rs2159776 0.143 0.291 0.367 0.598 13 rs17611, rs7040033, rs2416811, rs9657673, rs3736855 0.328 0.011 0.716 0.450 14 rs10985126 0.206 1.86E−04 0.103 0.992 15 rs1323472, rs7030849 0.585 1.99E−04 0.935 0.415 16 rs12683062 0.113 0.042 0.696 0.327 17 rs3747843 0.337 0.112 0.123 0.059 18 rs10760152, rs10081760 0.297 0.007 0.933 0.790 19 rs942152 0.434 2.92E−05 0.161 0.919 20 rs9408928, rs9409230 0.063 0.270 0.955 0.307 21 rs10985196, rs7046030, rs12683459 0.089 6.17E−06 0.001 — 22 rs306781 0.015 0.905 0.661 0.147 23 rs4837839 0.079 0.171 0.988 0.667 24 rs306783 0 0.192 0.210 0.987 25 rs306784 0.009 0.054 0.144 0.876 26 rs10818527 0.02 0.007 0.044 0.368 27 rs12683989 0.019 0.009 0.054 0.573 ^(a)SNPs were grouped together if their pairwise r² values were >0.90. The first SNP in each group was used for the analyses. With the exception of Groups 1 and 2, they are listed in the order of appearance on the chromosome (for groups of SNPs, the position of the first SNP was used). ^(b)Pairwise LD between rs7021049 and each of the 27 other SNPs as measured by r² in the cases and controls of the combined analysis of all three sample sets. ^(c)Univariate analysis using logistic regression.

TABLE 14 Global P-values for backwards and forwards models using logistic regression.^(a) Building Sample Tested Sample Sets Set Model SNPs^(b) 1 2 3 Combined 1 Forward rs10760117 0.0022 0.135 0.165 1.31E−22 2 Forward rs7021880, rs12683062, rs10985196, rs4837839, rs12683989 0.067 6.40E−10 0.419 7.38E−25 3 Forward rs2159776, rs1323472 0.051 0.084 0.0048 1.08E−22 Combined Forward rs7021049, rs10985196 0.010 8.25E−08 0.089 1.15E−27 1 Backward rs10985126, rs2269066, rs10760152, rs306781, rs1323472, rs1837 1.25E−04 5.82E−04 0.077 7.89E−23 2 Backward Same Model as Sample Set 2-Forward 0.067 6.40E−10 0.419 7.38E−25 3 Backward rs2159776, rs3747843, rs2269066, rs2269067, rs1323472 0.0963 0.0018 0.0037 4.33E−24 Combined Backward rs10818527, rs3747843, rs7021880, rs2269067, rs1323472 0.023 1.43E−06 0.063 5.61E−28 ^(a)Calculated using the log likelihood ratio test. ^(b)SNPs included in each model.

TABLE 15 RA risk estimates for 3 loci-HLA-SE , PTPN22 and TRAF1-assuming a disease prevalence of 1%, 10% and 30%. Disease Prevalence Loci 1% 10% HLA^(a) PTPN22^(b) TRAF1^(c) P(MLG)^(d) P(RA|MLG)^(e) RR^(f) SRR^(g) P(MLG)^(d) P(RA|MLG)^(e) RR^(f) SRR^(g) OSE CC AGT/AGT 0.189 0.003 0.29 (0.21-0.38) 1.00 0.176 0.031 0.31 (0.23-0.40) 1.00 OSE CC Other 0.269 0.004 0.41 (0.33-0.50) 1.41 0.254 0.043 0.43 (0.35-0.52) 1.39 OSE TT + TC AGT/AGT 0.039 0.005 0.50 (0.27-0.85) 1.73 0.037 0.053 0.53 (0.29-0.86) 1.70 OSE CC GCG/GCG 0.036 0.006 0.56 (0.30-0.94) 1.92 0.034 0.058 0.58 (0.32-0.94) 1.87 OSE TT + TC Other 0.055 0.007 0.71 (0.46-1.05) 2.44 0.054 0.073 0.73 (0.49-1.05) 2.35 OSE TT + TC GCG/GCG 0.007 0.010 0.96 (0.69-1.16) 3.33 0.007 0.097 0.97 (0.71-1.14) 3.12 1SE CC AGT/AGT 0.114 0.009 0.90 (0.29-3.26) 3.09 0.113 0.090 0.90 (0.31-2.70) 2.92 1SE CC Other 0.162 0.013 1.26 (1.05-1.53) 4.35 0.166 0.123 1.23 (1.04-1.46) 3.98 1SE TT + TC AGT/AGT 0.024 0.015 1.55 (0.92-2.70) 5.34 0.025 0.147 1.47 (0.94-2.34) 4.76 1SE CC GCG/GCG 0.022 0.017 1.71 (1.00-3.09) 5.92 0.023 0.161 1.61 (1.00-2.60) 5.20 1SE TT + TC Other 0.034 0.022 2.17 (1.48-3.37) 7.49 0.037 0.196 1.96 (1.41-2.77) 6.33 1SE TT + TC GCG/GCG 0.005 0.029 2.94 (1.11-13.91) 10.15 0.005 0.250 2.50 (1.10-6.40) 8.07 2SE CC AGT/AGT 0.014 0.043 4.29 (2.62-8.45) 14.82 0.019 0.330 3.30 (2.26-5.04) 10.67 2SE CC Other 0.021 0.060 5.95 (3.98-10.07) 20.55 0.030 0.410 4.10 (3.12-5.49) 13.26 2SE TT + TC AGT/AGT 0.003 0.072 7.23 (2.75-100) 24.95 0.005 0.462 4.62 (2.39-10) 14.90 2SE CC GCG/GCG 0.003 0.080 7.96 (2.94-100) 27.48 0.005 0.488 4.88 (2.58-10) 15.74 2SE TT + TC Other 0.004 0.099 9.91 (4.62-34.44) 34.20 0.008 0.547 5.47 (3.47-8.57) 17.68 2SE TT + TC GCG/GCG 0.0006 0.131 13.06 (NC)^(h) 45.10 0.001 0.623 6.23 (NC)^(h) 20.12 Disease Prevalence Loci 30% HLA^(a) PTPN22^(b) TRAF1^(c) P(MLG)^(d) P(RA|MLG)^(e) RR^(f) SRR^(g) OSE CC AGT/AGT 0.149 0.110 0.37 (0.27-0.46) 1.00 OSE CC Other 0.222 0.148 0.49 (0.41-0.59) 1.35 OSE TT + TC AGT/AGT 0.033 0.176 0.59 (0.34-0.89) 1.61 OSE CC GCG/GCG 0.031 0.192 0.64 (0.38-0.97) 1.75 OSE TT + TC Other 0.051 0.232 0.77 (0.55-1.04) 2.11 OSE TT + TC GCG/GCG 0.007 0.292 0.97 (0.36-1.96) 2.66 1SE CC AGT/AGT 0.110 0.277 0.92 (0.76-1.11) 2.53 1SE CC Other 0.175 0.351 1.17 (1.03-1.32) 3.20 1SE TT + TC AGT/AGT 0.027 0.400 1.33 (0.95-1.80) 3.65 1SE CC GCG/GCG 0.026 0.425 1.42 (1.00-1.91) 3.88 1SE TT + TC Other 0.045 0.485 1.62 (1.30-1.99) 4.42 1SE TT + TC GCG/GCG 0.007 0.563 1.88 (1.07-2.93) 5.13 2SE CC AGT/AGT 0.028 0.656 2.19 (1.76-2.65) 5.97 2SE CC Other 0.051 0.729 2.43 (2.12-2.75) 6.64 2SE TT + TC AGT/AGT 0.009 0.768 2.56 (1.83-3.33) 7.00 2SE CC GCG/GCG 0.009 0.786 2.62 (1.91-3.33) 7.16 2SE TT + TC Other 0.016 0.824 2.75 (2.25-3.19) 7.50 2SE TT + TC GCG/GCG 0.003 0.864 2.88 (NC)^(h) 7.88 ^(a)The number of copies of the HLA-DRB1 shared epitope (SE). SE⁺ H LA-DRB1 alleles include: 0101, 0102, 0401, 0404, 0405, 0408 and 1001. ^(b)The PTPN22 R620W genotype (CC indicates homozygosity for the protective R620 allele; TT + TC indicates carriage of the risk W620 allele). ^(c)The TRAF1 diplotype (allele 1 rs2239657-allele 1 rs7021880-allele 1 rs7021049/allele 2 rs2239657-allele 2 rs7021880-allele 2 rs7021049). ^(d)Probability of the indicated 3-locus genotype. ^(e)Probability of RA given the indicated 3-locus genotype. ^(f)Relative risk and 95% confidence intervals from Monte Carlo simulations using 10,000 replicates. ^(g)Standardized relative risk estimates setting the lowest value in each group to one. ^(h)95% CIs were not calculated due to small counts.

TABLE 16 HapMap SNPs in high LD (r² > 0.85) with rs7021049 and rs2239657. a. rs7021049^(a) SNP r² with rs7021049 Position^(b) Region rs10985070 0.967 122675942 PHF19 rs10985073 0.967 122683676 PHF19-TRAF1 intergenic rs10818482 0.967 122687906 PHF19-TRAF1 intergenic rs2072438 0.967 122691122 PHF19-TRAF1 intergenic rs10760126 1 122702439 PHF19-TRAF1 intergenic rs4836834 1 122705722 TRAF1 rs2416804 0.967 122716217 TRAF1 rs10118357 1 122719889 TRAF1 rs2269060 1 122723390 TRAF1 rs7037195 1 122723821 TRAF1 rs1014530 1 122724913 TRAF1 rs3761846 1 122729418 TRAF1-C5 intergenic rs3761847 0.967 122730060 TRAF1-C5 intergenic rs10760129 1 122740004 TRAF1-C5 intergenic rs10760130 1 122741811 TRAF1-C5 intergenic rs10818488 1 122744908 TRAF1-C5 intergenic b. rs2239657 SNP r² with rs2239657 Position^(b) Region rs1953126 0.934 122680321 5′ PHF19 rs1930778 0.96 122681190 PHF19-TRAF1 intergenic rs1609810 0.961 122682172 PHF19-TRAF1 intergenic rs7034390 0.934 122686309 PHF19-TRAF1 intergenic rs10760121 0.934 122687736 PHF19-TRAF1 intergenic rs2270231 0.934 122690803 PHF19-TRAF1 intergenic rs881375 0.934 122692719 PHF19-TRAF1 intergenic rs6478486 0.934 122695150 PHF19-TRAF1 intergenic rs1468671 0.966 122697323 PHF19-TRAF1 intergenic rs1860824 0.965 122699160 PHF19-TRAF1 intergenic rs7046108 0.966 122700160 PHF19-TRAF1 intergenic rs10435843 0.966 122707854 TRAF1 rs10435844 0.966 122708020 TRAF1 rs2239658 0.966 122711658 TRAF1 rs7021880 0.894 122713711 TRAF1 rs2416805 0.966 122716303 TRAF1 rs758959 0.966 122716520 TRAF1 rs876445 0.966 122716923 TRAF1 rs2109895 0.966 122717648 TRAF1 rs7021206 0.965 122723978 TRAF1 rs1014529 0.966 122724764 TRAF1 rs1930780 0.966 122726040 TRAF1 rs1930781 0.966 122727655 TRAF1 rs2416806 0.966 122730113 TRAF1-C5 intergenic rs7864019 0.966 122732689 TRAF1-C5 intergenic rs10739580 0.966 122735103 TRAF1-C5 intergenic rs10733648 0.966 122740600 TRAF1-C5 intergenic rs4837804 0.863 122745125 TRAF1-C5 intergenic rs7039505 1 122745766 TRAF1-C5 intergenic rs2900180 0.962 122746203 TRAF1-C5 intergenic ^(a)rs1930782 at position 122727726, which was genotyped in this study but not in the HapMap, is in strong LD with rs7021049 (r² > 0.95). ^(b)Positions according to genomic conting NT_008470.18 (Entrez Nucleotide). 

What is claimed is:
 1. A method of determining whether a human has an altered risk for rheumatoid arthritis, comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:526, 92-525, and 527-584 or its complement, wherein the polymorphism indicates an altered risk for rheumatoid arthritis.
 2. The method of claim 1, wherein the altered risk is an increased risk or a decreased risk.
 3. The method of claim 1, wherein said nucleic acid is a nucleic acid extract from a biological sample from said human.
 4. The method of claim 3, wherein said biological sample is blood, saliva, or buccal cells.
 5. The method of claim 3, further comprising preparing said nucleic acid extract from said biological sample prior to said testing step.
 6. The method of claim 3, further comprising obtaining said biological sample from said human prior to said preparing step.
 7. The method of claim 1, wherein said testing step comprises nucleic acid amplification.
 8. The method of claim 7, wherein said nucleic acid amplification is carried out by polymerase chain reaction.
 9. The method of claim 1, further comprising correlating the presence of the polymorphism with an altered risk for rheumatoid arthritis.
 10. The method of claim 9, wherein said correlating step is performed by computer software.
 11. The method of claim 1, wherein said testing is performed using sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, or denaturing gradient gel electrophoresis (DGGE).
 12. The method of any one of claim 1, wherein said testing is performed using an allele-specific method.
 13. The method of claim 12, wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification.
 14. The method of claim 1 which is an automated method.
 15. A method of determining whether a human has an altered risk for rheumatoid arthritis, comprising testing nucleic acid from said human for the presence or absence of a first polymorphism which is in linkage disequilibrium with a second polymorphism, wherein the second polymorphism is a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:92-584 or its complement, and wherein the first polymorphism indicates an altered risk for rheumatoid arthritis.
 16. The method of claim 15, wherein the altered risk is an increased risk or a decreased risk.
 17. The method of claim 15, wherein the first polymorphism is selected from the group consisting of the polymorphisms in Table
 4. 18. The method of claim 1, wherein said polymorphism comprises at least one polymorphism selected from the group consisting of rs2239657, rs7021880, and rs7021049.
 19. The method of claim 18, wherein said polymorphism comprises a haplotype selected from the group consisting of rs2239657(G)-rs7021880(C)-rs7021049(G) and rs2239657(A)-rs7021880(G)-rs7021049(T).
 20. The method of claim 19, wherein the rs2239657(G)-rs7021880(C)-rs7021049(G) haplotype indicates an increased risk for rheumatoid arthritis and the rs2239657(A)-rs7021880(G)-rs7021049(T) haplotype indicates a decreased risk for rheumatoid arthritis.
 21. The method of claim 18, wherein said polymorphism comprises a diplotype selected from the group consisting of rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) and rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T).
 22. The method of claim 21, wherein the rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) diplotype indicates an increased risk for rheumatoid arthritis and the rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T) diplotype indicates a decreased risk for rheumatoid arthritis.
 23. The method of claim 18, further comprising testing nucleic acid from said human for at least one other polymorphism selected from the group consisting of PTPN22 R620 W and HLA-DRB 1, wherein the PTPN22 R620 allele (CC genotype) and 0SE at HLA-DRB 1 indicate a decreased risk for rheumatoid arthritis, and the PTPN22 W620 allele (TT or TC genotype) and 2SE at HLA-DRB 1 indicate an increased risk for rheumatoid arthritis.
 24. A method of reducing the risk of rheumatoid arthritis in a human, comprising administering to said human an effective amount of a therapeutic agent, said human having been identified as having an increased risk for rheumatoid arthritis due to the presence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:92-584 or its complement.
 25. The method of claim 24, wherein said therapeutic agent comprises a TNF inhibitor.
 26. A method of reducing the risk of rheumatoid arthritis in a human, comprising: (a) identifying a human who has an increased risk for rheumatoid arthritis due to the presence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:92-584 or its complement; and (b) administering to said human an effective amount of a therapeutic agent, thereby reducing the risk of rheumatoid arthritis in said human.
 27. The method of claim 26, wherein said therapeutic agent comprises a TNF inhibitor.
 28. The method of claim 26, wherein step (a) comprises testing nucleic acid from said human for the presence or absence of said polymorphism.
 29. The method of claim 12 in which said testing is carried out by using an allele-specific primer selected from the group consisting of the allele-specific primers in Table
 3. 30. The method of claim 1, further comprising selecting said human for inclusion in a clinical trial of a therapeutic agent.
 31. The method of claim 30, wherein said therapeutic agent comprises a TNF inhibitor.
 32. A kit for carrying out the method of claim 1, wherein the kit comprises at least one polynucleotide detection reagent, and wherein the polynucleotide detection reagent selectively hybridizes to said nucleic acid in the presence of said polymorphism and does not hybridize to said nucleic acid in the absence of said polymorphism. 